Gene Report

Basic Information

Approved Symbol	RHOA
Approved Name	ras homolog family member A
Previous Symbol	ARH12, ARHA
Previous Name	ras homolog gene family, member A
Symbol Alias	RhoA, Rho12, RHOH12
Location	3p21.3
Position	chr3:49396578-49449526 (-)
External Links	Entrez Gene: 387 Ensembl: ENSG00000067560 UCSC: uc003cwu.3 HGNC ID: 667
No. of Studies (Positive/Negative)	1(1/0)
Type	Literature-origin

Positive relationships between RHOA and MDD (count: 0)

Positive relationships between RHOA and other components at different levels (count: 1)

Genetic/epigenetic locus					Protein and other molecule			Cell and molecular pathway			Neural system			Cognition and behavior		Symptoms and signs			Environment

Name in Literature	Level	Approved Name (Name in Literature)	Type	Reference	Research Type	Statistical Result	Relation Description	All
Name in Literature	Related Components
Rhoa		SLC17A7(vesicular glutamate transporter 1 (VGLUT1))	gene	Tordera RM, 2011	animal model		gene was regulated in frontal cortex of VGLUT1(+/-) mice gene was regulated in frontal cortex of VGLUT1(+/-) mice

Positive relationship network of RHOA in MK4MDD

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Note:
1. The different color of the nodes denotes the level of the nodes.

Genetic/Epigenetic Locus	Protein and Other Molecule	Cell and Molecular Pathway	Neural System	Cognition and Behavior	Symptoms and Signs	Environment	MDD

2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network. If the mapped gene or protein is not from literature, square node would be used instead of Circle node. Accordingly, the relationship is marked with dot line.
2. User can drag the nodes to rearrange the layout of the network. Click the node will enter the report page of the node. Right-click will show also the menus to link to the report page of the node and remove the node and related edges. Hover the node will show the level of the node and hover the edge will show the evidence/description of the edge.
3. The network is generated using Cytoscape Web

Negative relationships between RHOA and MDD (count: 0)

Negative relationships between RHOA and other components at different levels (count: 0)

RHOA related SNPs in MK4MDD (count: 0)

RHOA related proteins in MK4MDD (count: 1)

Approved Name	UniportKB	No. of Studies (Positive/Negative)	Source
Transforming protein RhoA	P61586	0(0/0)	Gene mapped

RHOA related GO terms (count: 77)

ID	Name	Type	Evidence
Literature-origin GO terms
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0005856	cytoskeleton	cellular component	IEA
GO:0030054	cell junction	cellular component	TAS

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0043297	apical junction assembly	biological process	IMP
GO:0051056	regulation of small GTPase mediated signal transduction	biological process	TAS
GO:0036089	cleavage furrow formation	biological process	IDA[16103226]
GO:0032587	ruffle membrane	cellular component	IEA
GO:0030521	androgen receptor signaling pathway	biological process	IEA
GO:0043524	negative regulation of neuron apoptotic process	biological process	IEA
GO:0005829	cytosol	cellular component	TAS
GO:0030334	regulation of cell migration	biological process	IMP[19934221]
GO:0043124	negative regulation of I-kappaB kinase/NF-kappaB cascade	biological process	IEA
GO:0007264	small GTPase mediated signal transduction	biological process	TAS
GO:0009612	response to mechanical stimulus	biological process	IEA
GO:0045471	response to ethanol	biological process	IEA
GO:0003924	GTPase activity	molecular function	TAS[10436159]
GO:0005634	nucleus	cellular component	IEA
GO:0005886	plasma membrane	cellular component	TAS
GO:0042346	positive regulation of NF-kappaB import into nucleus	biological process	NAS[12761501]
GO:0030335	positive regulation of cell migration	biological process	IEA
GO:0043296	apical junction complex	cellular component	IDA
GO:0007179	transforming growth factor beta receptor signaling pathway	biological process	TAS
GO:0031098	stress-activated protein kinase signaling cascade	biological process	IEA
GO:0045727	positive regulation of translation	biological process	IEA
GO:0043280	positive regulation of cysteine-type endopeptidase activity involved in apoptotic process	biological process	IEA
GO:0051496	positive regulation of stress fiber assembly	biological process	IDA[15467718]
GO:0030424	axon	cellular component	IEA
GO:0033144	negative regulation of intracellular steroid hormone receptor signaling pathway	biological process	IEA
GO:0030496	midbody	cellular component	IEA
GO:0045785	positive regulation of cell adhesion	biological process	IEA
GO:0019904	protein domain specific binding	molecular function	IEA
GO:0005739	mitochondrion	cellular component	IEA
GO:0051924	regulation of calcium ion transport	biological process	IEA
GO:0019048	virus-host interaction	biological process	IEA
GO:0001666	response to hypoxia	biological process	IEA
GO:0007519	skeletal muscle tissue development	biological process	IEA
GO:0043200	response to amino acid stimulus	biological process	IEA
GO:0045666	positive regulation of neuron differentiation	biological process	IMP[17488780]
GO:0051384	response to glucocorticoid stimulus	biological process	IEA
GO:0043123	positive regulation of I-kappaB kinase/NF-kappaB cascade	biological process	IEP[12761501]
GO:0030036	actin cytoskeleton organization	biological process	TAS[10436159]
GO:0050770	regulation of axonogenesis	biological process	TAS
GO:0045907	positive regulation of vasoconstriction	biological process	IEA
GO:0090307	spindle assembly involved in mitosis	biological process	IMP[19635168]
GO:0007411	axon guidance	biological process	TAS
GO:0030838	positive regulation of actin filament polymerization	biological process	IEA
GO:0048015	phosphatidylinositol-mediated signaling	biological process	TAS
GO:0050771	negative regulation of axonogenesis	biological process	TAS
GO:0050773	regulation of dendrite development	biological process	IEA
GO:0032154	cleavage furrow	cellular component	IEA
GO:0043149	stress fiber assembly	biological process	IEA
GO:0005938	cell cortex	cellular component	IDA[16103226]
GO:0005515	protein binding	molecular function	IPI[10051605]
GO:0017022	myosin binding	molecular function	IPI[15644318]
GO:0048011	nerve growth factor receptor signaling pathway	biological process	TAS
GO:0030168	platelet activation	biological process	TAS
GO:0007266	Rho protein signal transduction	biological process	TAS[10436159]
GO:0045665	negative regulation of neuron differentiation	biological process	IEA
GO:0050772	positive regulation of axonogenesis	biological process	TAS
GO:0061383	trabecula morphogenesis	biological process	ISS
GO:0030027	lamellipodium	cellular component	IEA
GO:0043931	ossification involved in bone maturation	biological process	ISS
GO:0042493	response to drug	biological process	IEA
GO:0009749	response to glucose stimulus	biological process	IEA
GO:0005525	GTP binding	molecular function	IEA
GO:0006357	regulation of transcription from RNA polymerase II promoter	biological process	IEA
GO:0071803	positive regulation of podosome assembly	biological process	IEA
GO:0007160	cell-matrix adhesion	biological process	IEA
GO:0071777	positive regulation of cell cycle cytokinesis	biological process	IMP[17115030]
GO:0043525	positive regulation of neuron apoptotic process	biological process	IEA
GO:0033688	regulation of osteoblast proliferation	biological process	ISS
GO:0007596	blood coagulation	biological process	TAS
GO:0030307	positive regulation of cell growth	biological process	IEA

RHOA related KEGG pathways (count: 15)

ID	Name	Brief Description	Full Description
Literature-origin KEGG pathway
hsa04270	vascular smooth_muscle_contraction	Vascular smooth muscle contraction	The vascular smooth muscle cell (VSMC) is a highly specializ...... The vascular smooth muscle cell (VSMC) is a highly specialized cell whose principal function is contraction. On contraction, VSMCs shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure. The principal mechanisms that regulate the contractile state of VSMCs are changes in cytosolic Ca2+ concentration (c). In response to vasoconstrictor stimuli, Ca2+ is mobilized from intracellular stores and/or the extracellular space to increase c in VSMCs. The increase in c, in turn, activates the Ca2+-CaM-MLCK pathway and stimulates MLC20 phosphorylation, leading to myosin-actin interactions and, hence, the development of contractile force. The sensitivity of contractile myofilaments or MLC20 phosphorylation to Ca2+ can be secondarily modulated by other signaling pathways. During receptor stimulation, the contractile force is greatly enhanced by the inhibition of myosin phosphatase. Rho/Rho kinase, PKC, and arachidonic acid have been proposed to play a pivotal role in this enhancement. The signaling events that mediate relaxation include the removal of a contractile agonist (passive relaxation) and activation of cyclic nucleotide-dependent signaling pathways in the continued presence of a contractile agonist (active relaxation). Active relaxation occurs through the inhibition of both Ca2+ mobilization and myofilament Ca2+ sensitivity in VSMCs. More...
hsa04360	axon guidance	Axon guidance	Axon guidance represents a key stage in the formation of neu...... Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as netrins, ephrins, Slits, and semaphorins. These guidance cues are read by growth cone receptors, and signal transduction pathways downstream of these receptors converge onto the Rho GTPases to elicit changes in cytoskeletal organization that determine which way the growth cone will turn. More...
hsa04810	regulation of_actin_cytoskeleton	Regulation of actin cytoskeleton
hsa04510	focal adhesion	Focal adhesion	Cell-matrix adhesions play essential roles in important biol...... Cell-matrix adhesions play essential roles in important biological processes including cell motility, cell proliferation, cell differentiation, regulation of gene expression and cell survival. At the cell-extracellular matrix contact points, specialized structures are formed and termed focal adhesions, where bundles of actin filaments are anchored to transmembrane receptors of the integrin family through a multi-molecular complex of junctional plaque proteins. Some of the constituents of focal adhesions participate in the structural link between membrane receptors and the actin cytoskeleton, while others are signalling molecules, including different protein kinases and phosphatases, their substrates, and various adapter proteins. Integrin signaling is dependent upon the non-receptor tyrosine kinase activities of the FAK and src proteins as well as the adaptor protein functions of FAK, src and Shc to initiate downstream signaling events. These signalling events culminate in reorganization of the actin cytoskeleton; a prerequisite for changes in cell shape and motility, and gene expression. Similar morphological alterations and modulation of gene expression are initiated by the binding of growth factors to their respective receptors, emphasizing the considerable crosstalk between adhesion- and growth factor-mediated signalling. More...

ID	Name	Brief Description	Full Description
Gene mapped KEGG pathways
hsa04660	t cell_receptor_signaling_pathway	T cell receptor signaling pathway	Activation of T lymphocytes is a key event for an efficient ...... Activation of T lymphocytes is a key event for an efficient response of the immune system. It requires the involvement of the T-cell receptor (TCR) as well as costimulatory molecules such as CD28. Engagement of these receptors through the interaction with a foreign antigen associated with major histocompatibility complex molecules and CD28 counter-receptors B7.1/B7.2, respectively, results in a series of signaling cascades. These cascades comprise an array of protein-tyrosine kinases, phosphatases, GTP-binding proteins and adaptor proteins that regulate generic and specialised functions, leading to T-cell proliferation, cytokine production and differentiation into effector cells. More...
hsa05210	colorectal cancer	Colorectal cancer	Classically, colorectal cancer (CRC) has been believed to de...... Classically, colorectal cancer (CRC) has been believed to develop from normal mucosa through the premalignant adenoma by the step-wise accumulation of mutations. All CRC display either microsatellite instability (MSI) or chromosome instability (CIN). MSI occurs in 15% of colon cancers and results from inactivation of the DNA mismatch repair (MMR) system by either MMR gene mutations or hypermethylation of the MLH1 promoter. MSI promotes tumorigenesis through generating mutations in target genes that possess coding microsatellite repeats, such as beta-catenin, TGFBR2 and BAX. CIN is found in the majority of colon cancers and leads to a different pattern of gene alterations that contribute to tumor formation. Genes involved in CIN are those coding for APC, K-ras, SMAD4 and p53. More...
hsa04350	tgf beta_signaling_pathway	TGF-beta signaling pathway	The transforming growth factor-beta (TGF-beta) family member...... The transforming growth factor-beta (TGF-beta) family members, which include TGF-betas, activins and bone morphogenetic proteins (BMPs), are structurally related secreted cytokines found in species ranging from worms and insects to mammals. A wide spectrum of cellular functions such as proliferation, apoptosis, differentiation and migration are regulated by TGF-beta family members. TGF-beta family member binds to the Type II receptor and recruits Type I, whereby Type II receptor phosphorylates and activates Type I. The Type I receptor, in turn, phosphorylates receptor-activated Smads ( R-Smads: Smad1, Smad2, Smad3, Smad5, and Smad8). Once phosphorylated, R-Smads associate with the co-mediator Smad, Smad4, and the heteromeric complex then translocates into the nucleus. In the nucleus, Smad complexes activate specific genes through cooperative interactions with other DNA-binding and coactivator (or co-repressor) proteins. More...
hsa04062	chemokine signaling_pathway	Chemokine signaling pathway	Inflammatory immune response requires the recruitment of leu...... Inflammatory immune response requires the recruitment of leukocytes to the site of inflammation upon foreign insult. Chemokines are small chemoattractant peptides that provide directional cues for the cell trafficking and thus are vital for protective host response. In addition, chemokines regulate plethora of biological processes of hematopoietic cells to lead cellular activation, differentiation and survival. The chemokine signal is transduced by chemokine receptors (G-protein coupled receptors) expressed on the immune cells. After receptor activation, the alpha- and beta-gamma-subunits of G protein dissociate to activate diverse downstream pathways resulting in cellular polarization and actin reorganization. Various members of small GTPases are involved in this process. Induction of nitric oxide and production of reactive oxygen species are as well regulated by chemokine signal via calcium mobilization and diacylglycerol production. More...
hsa04530	tight junction	Tight junction	Epithelial tight junctions (TJs) are composed of at least th...... Epithelial tight junctions (TJs) are composed of at least three types of transmembrane protein -occludin, claudin and junctional adhesion molecules (JAMs)- and a cytoplasmic 'plaque' consisting of many different proteins that form large complexes. The transmembrane proteins mediate cell adhesion and are thought to constitute the intramembrane and paracellular diffusion barriers. The cytoplasmic 'plaque' contains three major multi-protein complexes consisting largely of scaffolding proteins, the ZO protein complex, the CRB3-Pals1-PATJ complex and the PAR-3-aPKC-PAR-6 complex. The ZO protein complex appears to organize the transmembrane proteins and couple them to other cytoplasmic proteins and to actin microfilaments. Two evolutionarily conserved protein complexes, the CRB3 and PAR complexes are involved in the establishment and maintenance of epithelial cell polarity. Besides these three protein complexes which seem to be constitutively associated at TJs, a number of proteins with different functions has been identified at TJs. These include additional scaffolding proteins like MUPP1 and MAGI-1, adaptor proteins, transcription regulators and RNA processing factors, regulatory proteins like small GTPases and G-proteins, kinases and phosphatases, and heat shock proteins. These are proposed to be involved in junction assembly, barrier regulation, gene transcription, and perhaps other, presently undefined pathways. More...
hsa05200	pathways in_cancer	Pathways in cancer
hsa04520	adherens junction	Adherens junction	Cell-cell adherens junctions (AJs), the most common type of ...... Cell-cell adherens junctions (AJs), the most common type of intercellular adhesions, are important for maintaining tissue architecture and cell polarity and can limit cell movement and proliferation. At AJs, E-cadherin serves as an essential cell adhesion molecules (CAMs). The cytoplasmic tail binds beta-catenin, which in turn binds alpha-catenin. Alpha-catenin is associated with F-actin bundles directly and indirectly. The integrity of the cadherin-catenin complex is negatively regulated by phosphorylation of beta-catenin by receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases (Fer, Fyn, Yes, and Src), which leads to dissociation of the cadherin-catenin complex. Integrity of this complex is positively regulated by beta -catenin phosphorylation by casein kinase II, and dephosphorylation by protein tyrosine phosphatases. Changes in the phosphorylation state of beta-catenin affect cell-cell adhesion, cell migration and the level of signaling beta-catenin. Wnt signaling acts as a positive regulator of beta-catenin by inhibiting beta-catenin degradation, which stabilizes beta-catenin, and causes its accumulation. Cadherin may acts as a negative regulator of signaling beta-catenin as it binds beta-catenin at the cell surface and thereby sequesters it from the nucleus. Nectins also function as CAMs at AJs, but are more highly concentrated at AJs than E-cadherin. Nectins transduce signals through Cdc42 and Rac, which reorganize the actin cytoskeleton, regulate the formation of AJs, and strengthen cell-cell adhesion. More...
hsa04722	neurotrophin signaling_pathway	Neurotrophin signaling pathway	Neurotrophins are a family of trophic factors involved in di...... Neurotrophins are a family of trophic factors involved in differentiation and survival of neural cells. The neurotrophin family consists of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4 (NT-4). Neurotrophins exert their functions through engagement of Trk tyrosine kinase receptors or p75 neurotrophin receptor (p75NTR). Neurotrophin/Trk signaling is regulated by connecting a variety of intracellular signaling cascades, which include MAPK pathway, PI-3 kinase pathway, and PLC pathway, transmitting positive signals like enhanced survival and growth. On the other hand, p75NTR transmits both positive and nagative signals. These signals play an important role for neural development and additional higher-order activities such as learning and memory. More...
hsa04670	leukocyte transendothelial_migration	Leukocyte transendothelial migration	Leukocyte migaration from the blood into tissues is vital fo...... Leukocyte migaration from the blood into tissues is vital for immune surveillance and inflammation. During this diapedesis of leukocytes, the leukocytes bind to endothelial cell adhesion molecules (CAM) and then migrate across the vascular endothelium. A leukocyte adherent to CAMs on the endothelial cells moves forward by leading-edge protrusion and retraction of its tail. In this process, alphaL /beta2 integrin activates through Vav1, RhoA, which subsequently activates the kinase p160ROCK. ROCK activation leads to MLC phosphorylation, resulting in retraction of the actin cytoskeleton. Moreover, Leukocytes activate endothelial cell signals that stimulate endothelial cell retraction during localized dissociation of the endothelial cell junctions. ICAM-1-mediated signals activate an endothelial cell calcium flux and PKC, which are required for ICAM-1 dependent leukocyte migration. VCAM-1 is involved in the opening of the endothelial passage through which leukocytes can extravasate. In this regard, VCAM-1 ligation induces NADPH oxidase activation and the production of reactive oxygen species (ROS) in a Rac-mediated manner, with subsequent activation of matrix metallopoteinases and loss of VE-cadherin-mediated adhesion. More...
hsa05130	pathogenic escherichia_coli_infection	Pathogenic Escherichia coli infection	Eenteropathogenic E. coli (EPEC) and enterohemorrhagic E. co...... Eenteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) are closely related pathogenic strains of Escherichia coli. The hallmark of EPEC/EHEC infections is induction of attaching and effacing (A/E) lesions that damage intestinal epithelial cells. The capacity to form A/E lesions is encoded mainly by the locus of enterocyte effacement (LEE) pathogenicity island. Tir, Map, EspF, EspG are known LEE-encoded effector proteins secreted via the type III secretion system, which is also LEE-encoded, into the host cell. EPEC and EHEC Tir's link the extracellular bacterium to the cell cytoskeleton. Map and EspF are involved in mitochondrion membrane permeabilization. EspG interacts with tubulins and stimulates microtubule destabilization. LEE-encoded adhesin or intimin (Eae) is exported via the general secretory pathway to the periplasm, where it is inserted into the outer membrane. In addition to Tir, two potential host cell-carried intimin receptors, beta1 integrin (ITGB1) and nucleolin (NCL), have so far been identified. The distinguishing feature of EHEC is the elaboration of Shiga-like toxin (Stx). Stx cleaves ribosomal RNA, thereby disrupting protein synthesis and killing the intoxicated epithelial or endothelial cells. More...
hsa04310	wnt signaling_pathway	Wnt signaling pathway	Wnt proteins are secreted morphogens that are required for b...... Wnt proteins are secreted morphogens that are required for basic developmental processes, such as cell-fate specification, progenitor-cell proliferation and the control of asymmetric cell division, in many different species and organs. There are at least three different Wnt pathways: the canonical pathway, the planar cell polarity (PCP) pathway and the Wnt/Ca2+ pathway. In the canonical Wnt pathway, the major effect of Wnt ligand binding to its receptor is the stabilization of cytoplasmic beta-catenin through inhibition of the bea-catenin degradation complex. Beta-catenin is then free to enter the nucleus and activate Wnt-regulated genes through its interaction with TCF (T-cell factor) family transcription factors and concomitant recruitment of coactivators. Planar cell polarity (PCP) signaling leads to the activation of the small GTPases RHOA (RAS homologue gene-family member A) and RAC1, which activate the stress kinase JNK (Jun N-terminal kinase) and ROCK (RHO-associated coiled-coil-containing protein kinase 1) and leads to remodelling of the cytoskeleton and changes in cell adhesion and motility. WNT-Ca2+ signalling is mediated through G proteins and phospholipases and leads to transient increases in cytoplasmic free calcium that subsequently activate the kinase PKC (protein kinase C) and CAMKII (calcium calmodulin mediated kinase II) and the phosphatase calcineurin. More...

RHOA related BioCarta pathways (count: 15)

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
TFF_PATHWAY	tff pathway	Trefoil Factors Initiate Mucosal Healing	Maintaining the integrity of the gastrointestinal tract desp...... Maintaining the integrity of the gastrointestinal tract despite the continual presence of microbial flora and injurious agents is essential. Epithelial repair requires restitution and regeneration. During restitution, epithelial cells spread and migrate across the basement membrane to re-establish surface-cell continuity, a process that is independent of cell proliferation. Epithelial continuity depends on a family of small abundant secreted proteins, the trefoil factors (TFFs). The trefoil factor (TFF) family comprises the gastric peptides pS2/TFF1 and spasmolytic peptide (SP)/TFF2, and the intestinal trefoil factor (ITF)/TFF3. Their fundamental action is to promote epithelial-cell restitution within the gastrointestinal tract. TFFs are abundantly secreted onto the mucosal surface by mucus-secreting cells. Their expression is rapidly and coordinately upregulated at the margins of mucosal injury. Secreted TFF acts on adjacent mucosal cell populations either extracellularly (augmenting barrier function) or intracellularly (transcriptional and signalling events). TFF response elements in TFF gene promoters allow increases in TFF expression through auto-induction and cross-induction of other TFFs, in addition to mucin expression and possibly tumor suppression. Cell migration is the result of integrated disruption of cellcell and cellsubstratum adhesion and prevention of apoptosis through cell detachment. Epithelial movement therefore requires integration of motogenic and cell-survival signals. This is achieved by activation of several intracellular signalling pathways that converge on ERK/MAPK and possibly NF-B activation. Serine phosphorylation of the extracellular signal-regulated kinases (ERKs)/mitogen-activated protein kinases (MAPKs) 1 and 2 is central to trefoil factor -mediated signalling, lying downstream of EGFR activation and possibly FAK activation (through recruitment of GRB2 and SOS). Cell migration might result from cooperation between ERK/MAPKs and Rho proteins, FAK activation, beta-integrin clustering and beta-catenin activation. Abrogation of cell death has been shown to require both PI3K activation and ERK/MAPK activation; the former operates through serine/threonine phosphorylation of AKT/protein kinase B, serine phosphorylation of BAD (BCL-2 agonist of cell death) and inhibition of mitochondrial cytochrome c release and formation of the apoptosome (APAF1, caspase-9 (CASP9) and cytochrome c (CYT-c). Translocation of phosphorylated ERK/MAPK to the nucleus leads to amplification and de-restriction of TFF expression to ensure sustained action. More...
RHO_PATHWAY	rho pathway	Rho cell motility signaling pathway	RhoA is a small G-protein in the Rho family that regulates c...... RhoA is a small G-protein in the Rho family that regulates cell morphology via actin cytoskeleton reorganization in response to extracellular signals. The majority of RhoA activations is due to disruption of intramolecular autoinhibitory interactions. Changes in cytoskeletal structure and other aspects of cell structure are involved in cell morphology. RhoA is activated by GEF factors, and repressed by GAPs. GEFs are guanine nucleotide exchange factors. GAPs are GTPase-activating proteins. The RhoGAP ARHGAP1 also acts as a GAP for Rac and CDC42. Active RhoA increases the stability of actin-based structures such as stress fibers and focal adhesions. Several different factors downstream of RhoA act on cytoskeletal structures to affect stability of these structures. Rock1 provides a direct link from RhoA to cell morphology through phosphorylation of the myosin light chain. Rock1 also phosphorylates and activates LIM kinase, which phosphorylates cofilin. Cofilin stimulates actin depolymerization and changes in cell structure, and phosphorylation of cofilin by LIM kinase represses this activity. According to Nimnual et al. Rho activity is reduced as a result of Rac-induced redox-dependent inhibition. Related Disease: Non-syndromic deafness appears to be the result of amino acid substitutions in the 52-amino acid C-terminal end of Dia 1. This modification creates a constituatively active Dia 1 protein. A mutation in the RhoGAP Oligophrenin-1 is thought to contribute to a form of mental retardation due to loss of Rho inhibition in neuronal development. More...
MAL_PATHWAY	mal pathway	Role of MAL in Rho-Mediated Activation of SRF	Serum response factor (SRF) is a transcription factor, which...... Serum response factor (SRF) is a transcription factor, which binds to a serum response element (SRE) associated with a variety of genes including (i)immediate early genes such as c-fos, fosB, junB, egr-1 and -2, (ii)neuronal genes such as nurr1 and nur77, and (iii)muscle genes such as actins and myosins. By regulating expression of these genes, SRF controls cell growth and differentiation, neuronal transmission as well as muscle development and function. SRF can be activated by serum, lysophosphatidic acid (LPA), lipopolysaccharide (LPS), 12-O-tetradecanoylphorbol-13-acetate (TPA), cytokines, tumor necrosis factor-alpha (TNFalpha), agents that increase intracellular Ca2+, T-cell virus1 activator protein, hepatitis B virus activator proteins pX, activated oncogenes and protooncogenes and extracellular stimuli such as antioxidant and UV light. In serum-starved cells, MAL is predominantly cytoplasmic where it is sequestered by actin monomers. Upon serum stimulation, Rho becomes active and, through its interaction with ROCK and mDia1, causes an accumulation of F-actin and a commensurate decrease in the level of G-actin. As a consequence, MAL is no longer sequestered and is free to translocate to the nucleus where it associates with SRF and activates SRE-mediated gene expression. More...
RAS_PATHWAY	ras pathway	Ras Signaling Pathway	Ras activates many signaling cascades. Here we illustrate so...... Ras activates many signaling cascades. Here we illustrate some of the well-characterized cascades in a generic compilation of effector molecules. The effectors mediate Ras stimulation to a diverse set of cellular signals. Many of these signals are interpreted differently depending on the cell type or microenvironment receiving the stimulus. Not all of these effectors are activated in any given cell type. The primary method of activation is to promote the translocation of the molecule to the plasma membrane where additional interactions lead to the activation of the molecule. RalGDS is a Guanine Exchange Factor (GEF) for Ral but also has other independent functions. RalGDS activates RalA/B-related small GTPases. RalBP1 is a GTPase activating protein that leads to the inhibition of the Rac and CDC42 GTPases. Ral can also interact with phospholipase D1 (PLD1) that can also be activated by RhoA. Ras stimulation of the lipid kinase activity of PI3K occurs through an interaction with the p110 catalytic subunit. PI3K phosphorylates the D3 position of phosphatidylinositides. In this example Pip2 is converted to PIP3. PIP3 stimulates the AKT/PKB kinase and several of the Rac-GEFs such as Sos1 AND Vav. AKT activation inhibits apoptosis by inhibiting the actions of Bad, Caspase9 and AFX. AKT further hinders apoptosis by phosphorylating the IkB repressor of NFkB. Stimulus of Rac causes among other things the activation of NFkB. Ras also stimulates the mitogen-activated kinases ERK1/2 via the Raf1 cascade. The Erk kinases translocate to the nucleus where they phosphorylate various transcription factors such as ELK1 More...
PAR1_PATHWAY	par1 pathway	Thrombin signaling and protease-activated receptors	Thrombin is an extracellular protease that is involved in th...... Thrombin is an extracellular protease that is involved in the clotting of blood and inflammation through its action on platelets and endothelial cells in the vasculature and that plays a role in thrombosis and myocardial infarction. The protease activated receptors PAR1 and PAR4 are cellular targets of thrombin signaling and members of the G-protein coupled receptor gene family. Both of these receptors are cleaved in their N-terminus by thrombin, unmasking a portion of the receptor sequence that acts itself as a tethered peptide ligand that activates the receptor. The tethered ligand that activates PAR1 is SFLLRN and the tethered ligand that activates PAR4 is GYPGQV. Other members of the family include PAR2 which is activated by trypsin rather than thrombin and PAR3 which seems to play a role in the activation of other PARs but does not itself transduce a signal directly. Addition of peptide agonist exogenously in solution can also activate PAR1, PAR2 and PAR4. PAR1 activation may be involved in the dilation of arteries during inflammation through the action of thrombin on endothelial cells and in platelet activation by thrombin during clotting. PAR1 and PAR2 activation cause bronchodilation in airway and may protect against asthma. PAR 4 activation by thrombin activates platelets during clotting and mice lacking PAR4 have impaired clotting and platelets that do not respond to thrombin signaling. The action of thrombin on PAR1 and PAR4 on platelets and endothelial cells may also contribute to vascular permeability and inflammation. Activated PARs appear to couple primarily through Gq-mediated stimulation of inositol phosphate metabolism and intracellular calcium levels to activate platelets. PAR1 and PAR4 also appear to couple to multiple G-proteins and transduce signals through more than one G-protein mediated pathway in some circumstances. Signaling by PAR1 and PAR4 through Galpha12 pathways couples to Rho signaling and changes in cytoskeletal structure and cell shape. Gi activation does not appear necessary for platelet activation by PAR1 or PAR4, and platelet activation by these receptors requires an ADP signal perhaps acting through the platelet-associated purinergic receptor P2Y12. Gi-coupled signaling may play a role in mitogenic PAR signaling in some settings through Map kinase activation. Activation of Rho by PAR1 can induce cellular transformation through a Galpha12 mediated mechanism and sustained rho-dependent phosphorylation of the myosin light chain by PAR1 contributes to cytoskeletal changes and activation of platelets. Since the activation of PARs by protease cleavage is irreversible the primary mechanism for down-regulation of the PAR signaling cascade appears to be internalization and degradation of PAR receptors. More...
EDG1_PATHWAY	edg1 pathway	Phospholipids as signalling intermediaries	Sphingosine-1-phosphate (S1P) is an example of lipid messeng...... Sphingosine-1-phosphate (S1P) is an example of lipid messengers with both intracellular and extracellular functions. Intracellularly S1P regulates proliferation and survival; extracellularly S1P is a ligand for EDG1 (also known as S1P1). Activation of sphingosine kinase (SPHK), the enzyme that catalyzes the phosphorylation of sphingosine, increases cellular levels of S1P. Inhibitors of SPHK block formation of S1P and inhibit cellular proliferation induced by a variety of factors, including as an example platelet-derived growth factor (PDGF) and PMA. In a study using endothelial cells it was demonstrated that S1P induces activation of alpha-v and B3 integrins via RhoA. S1P also activates Akt via Gi and PI3K. The activated Akt phosphorlyates the Edg1 receptor on threonine 236 leading to the activation of Rac1 and subsequent signals leading to actin assembly, chemotaxis and lamellipodia formation. Edg1 stimulation also leads to the activation of the ERK signaling cascade resulting in anti-apoptotic reversal, proliferation and cell survival. More...
CDC42RAC_PATHWAY	cdc42rac pathway	Role of PI3K subunit p85 in regulation of Actin Organization and Cell Migration	Migration of cells is involved in essential functions such a...... Migration of cells is involved in essential functions such as development, invasiveness of cancer cells, leukocyte movement toward chemotactic signals, and fibroblast response to injury. Cells can migrate in a specific direction in response to extracellular signals through pathways that trigger changes in the cytoskeleton, particularly actin filaments, increasing lamellipodia and filopodia formation and decreasing focal adhesions. Factors like PDGF activate PI3 kinase and multiple pathways downstream to stimulate cell migration. One pathway regulating migration through the p85 regulatory subunit of PI3 kinase does not require PI3-kinase activity. In this pathway, p85 of PI3-kinase activates cdc42, which activates N-Wasp (Wiskott-Aldrich Syndrome Protein) to regulate ARP-2/3. ARP-2/3 is a complex of proteins localized at the leading edge of moving cells that nucleates the formation of new actin fibers and interacts with Wasp to stimulate migration. The cdc42 pathway also regulates p21-activate kinase 1 (PAK1). Another pathway by which PI3 kinase regulates migration is through the small GTPase Rac. PAK1 is a downstream target of Rac as well as cdc42. Downstream of Rac and PAK1, Myosin light chain kinase (MLCK) phosphorylates myosin light chain to increase cell migration. The regulation of the localization and activity of signaling factors creates coordinated pathways linking extracellular signals and cellular migration. More...
INTEGRIN_PATHWAY	integrin pathway	Integrin Signaling Pathway	Integrins are cell surface receptors that interact with the ...... Integrins are cell surface receptors that interact with the extracellular matrix and mediate intracellular signals in response to the extracellular matrix including cellular shape, mobility, and progression through the cell cycle. Integrins do not themselves possess a kinase domain or enzymatic activity but rely on association with other signaling molecules to transmit signals. Interactions between the extracellular matrix and the actin cytoskeleton commonly take place at focal adhesions on the cell surface that contain localized concentrations of integrins, signaling molecules, and cytoskeletal elements. Talin forms a direct interaction with the integrin cytoplasmic domain, and interacts with cytoskeletal elements (actin) and signaling factors. Paxillin and CAS also localize in focal adhesions and may serve as a scaffold for other integrin signaling components like FAK and src. Interaction of FAK, CAS and src may be required for integrin regulation of cell cycle progression. The CrkL adaptor protein may regulate downstream integrin signaling. Growth factor signaling pathways and the caveolin receptor exhibit important cross talk with integrin receptors in cellular responses like activation of map kinase, proliferation and motility. More...
UCALPAIN_PATHWAY	ucalpain pathway	uCalpain and friends in Cell spread	The mammalian calpain gene family curently contains 13 disti...... The mammalian calpain gene family curently contains 13 distinct large subunit products most of which complex with one of two smaller 30kDa subunits. ( An excellent introduction to the Calpain family can be found on a web site created by Valery Thompson http://ag.arizona.edu/calpains/index.html ) Spreading cells display newly transiently formed integrin adhesion clusters containing Calpain1 (mu-Calpain), cleaved Talin, B3-Integrin and SPTAN1(Spectrin). Recruitment of Rac to these clusters leads to the activation of Rac and the formation of Rac-induced Focal clusters. The Calpain1 in the integrin clusters initially inactivates RhoA allowing for the formation of lamellipodia. The subsequent activation of newly synthesized RhoA transforms these clusters into Focal Adhesion Complexes and the formation of contractile actin-myosin stress fibers. These mature adhesions do not contain calpain. More...
AKAP13_PATHWAY	akap13 pathway	Rho-Selective Guanine Exchange Factor AKAP13 Mediates Stress Fiber Formation	The A-kinase anchor protein 13 (AKAP13, also known as AKAP-L...... The A-kinase anchor protein 13 (AKAP13, also known as AKAP-LBC) is one of a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. AKAP13 is a splice variant of the oncogene Lbc. Alternative splicing of the AKAP13 gene results in at least 3 transcript variants encoding different isoforms containing a Dbl oncogene homology (DH) domain and a pleckstrin homology (PH) domain. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. These splice variants contain a fragment that was originally identified as Ht31 which acts as a scaffolding protein to regulate the Rho signaling pathway and as protein kinase A-anchoring protein creating a coordination of these two signalling pathways. Diviani et al. found that in HEK293 cells LPA induced stimulation preferentially activates AKAP13 via G-alpha12. As yet targets for the anchored PKA have not been identified. AKAP13 and Rho do not appear to be phosphorylated by PKA. Diviani et al also found that the Lbc oncogene and protooncogene splice variant show higher activation and stress fiber localization. This appears to be a result of the presence of N terminal inhibitory sequences. A similar model of regulation has been proposed for Dbl and Vav. More...
CCR3_PATHWAY	ccr3 pathway	CCR3 signaling in Eosinophils	Eosinophils are a key class of leukocytes involved in inflam...... Eosinophils are a key class of leukocytes involved in inflammatory responses, including allergic reactions in skin and airway. The eosinophil response in inflammation is absent in mice lacking CCR3, indicating the key role of this G protein coupled receptor in inflammation and allergic responses. Eotaxin is a chemokine ligand for CCR3 that recruits eosinophils to the site of inflammation and activates them. Other chemokine ligands of CCR3 include eotaxin-2, MCP-3, MCP-4, and RANTES. Multiple signaling pathways activated by CCR3 participate in the inflammatory response of eosinophils. Eotaxin stimulates intracellular calcium release, production of reactive oxygen species, and changes in actin polymerization through a pertussis sensitive pathway. Rho and ROCK regulate actin stress fiber formation and are required for eosinophil chemotaxis. Rho is a G protein that activates ROCK, a protein kinase. Map kinase pathways are also involved in chemotaxis. Another key action of activated eosinophils is the release of reactive oxygen species, causing tissue damage during chronic inflammatory responses. Blocking eosinophil activation and the signaling pathways that lead to chemotaxis, degranulation and reactive oxygen release may alleviate inflammatory conditions and inflammation-associated tissue damage. More...
ECM_PATHWAY	ecm pathway	Erk and PI-3 Kinase Are Necessary for Collagen Binding in Corneal Epithelia	Activation of the MAPK kinase pathway has been identified as...... Activation of the MAPK kinase pathway has been identified as a mechanism that integrins use to regulate gene expression leading to cell shape changes during cell spreading or migration Epithelial cells respond to extracellular matrix (ECM) cause integrin-mediated FAK phosphorylation that in turn phosphorylates the surrounding proteins (paxillin, Fyn/shc, and src) and leads to signal amplification. FAK also binds PI-3 kinase and is upstream of the MAP kinase pathway. When MAPkinase or PI-3 kinase was inhibited, actin reorganization was blocked. Src phosphorylates p190RhoGAP, inactivating its GAP function that may allow RhoGTP to stay active longer, promoting further signal amplification. Activated RhoGTP binds to downstream kinases such as Rho-associated coiled coil-containing protein kinase (p160ROCK) and p140 diaphanous (p140Dia) to increase actin polymerization and contraction. Actin reorganization assists integrin clustering, allowing more ECM binding that increase FAK phosphorylation and other signal transduction events. More...
CARDIACEGF_PATHWAY	cardiacegf pathway	Role of EGF Receptor Transactivation by GPCRs in Cardiac Hypertrophy	One of responses to increased blood pressure is cardiac hype...... One of responses to increased blood pressure is cardiac hypertrophy through increased size of ventricular myocardial cells leading to increased thickness of the ventricular walls. Cardiac hypertrophy allows the heart to handle the increased stress caused by elevated blood pressure but is also a risk factor associated with heart disease. Cardiac hypertrophy results from cross-talk between G-protein coupled receptor signaling and the EGF receptor pathway. Several GPCR ligands are known to stimulate cardiac hypertrophy, including factors that regulate blood pressure such as angiotensin II and endothelin- 1. These factors stimulate phospholipase C through Gq activation, and the production of 1P3 and diacylglycerol second messengers. PKC-delta is activated by DAG and interacts with the metalloproteinase ADAM12. ADAM12 cleaves the membrane-bound HB-EGF to release soluble EGF ligand that activates EGF receptor in myocardial cells. EGF receptor activation downstream through small G proteins and the MAP kinase pathway ultimately leads to cardiac hypertrophy. Signals by GPCR ligands such as angiotensin II result in transcriptional translation of immediate early genes like fos and other genes involved in long-term remodeling of heart tissue and the physiological response to stress in the heart such as the atrial natriuretic factor. Factors such as the AKT kinase, reactive oxygen species (ROS) and NE-kB also are involved in signaling that leads to hypertrophy, although their role is not yet clear. Blocking this pathway at various steps may prevent heart disease through the prevention of cardiac hypertrophy, but may also have other consequences. More...
RACCYCD_PATHWAY	raccycd pathway	Influence of Ras and Rho proteins on G1 to S Transition	The cell cycle transition from G1 to S phase is a key regula...... The cell cycle transition from G1 to S phase is a key regulatory point in the cell cycle. This transition is regulated by the checkpoint kinase cdk2 that activates the G1 to S transition when it is associated with cyclin E. Cdk2/Cyclin E causes the G1 to S transition through phosphorylation of the tumor suppressor Rb, releasing the transcription factor E2F-1. Other pathways acting through Rac, Ras and Rho also regulate the G1 to S transition. Ras regulates cyclin D1 expression to affect the G1 to S transition. Transforming forms of Ras or Raf induce cyclin D1 expression and cause early entry into S phase. Signaling from Ras to Raf to MEK to ERKs induces Cyclin D1 expression, allowing Cyclin D1 to complex with Cdk4 and Cdk6 and phosphorylate Rb. Rac-1 and PAK appear to induce Cyclin D1 expression and induce the G1 to S transition primarily through activation of NF-kB to activate the Cyclin D1 promoter. Rho activates cdk2 and also inhibits p21 and p27 to induce cyclin D1 and stimulate the G1 to S transition. Rho represses p21 expression to block p21 induction by Ras and to allow Ras induced progression from G1 to S. Cells that lack p21 do not require Rho for Ras to induce cell cycle progression from G1 to S phase. The cooperative action of Ras, Rac and Rho to induce Cyclin D1 expression is a key component of oncogenic transformation. More...
AKAPCENTROSOME_PATHWAY	akapcentrosome pathway	Protein Kinase A at the Centrosome	Protein kinase A regulatory subunit RIIalpha (PKA-RIIa) is t...... Protein kinase A regulatory subunit RIIalpha (PKA-RIIa) is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP350 (also known as AKAP450 and CGNAP), MAP2 and Pericentrin. This diagram illustrates these three PKA-RII binding complexes. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate PKA-RIIa on T54 and this has been proposed to alter the subcellular localization of PKA-RIIa at the on set of mitosis. It has been demonstrated that PKA-RIIa dissociates and redistributes from centrosomes at mitosis. The focal point of this illustration is the AKAP350 complex. In addition to binding PKA-RIIa, AKAP350 binds PKN (Takahashi et al 1999) and the phosphatases PP1 and PPA2 (Takahashi et al 1999). PKN is a serine/threonine protein kinase, having a catalytic domain homologous to the PKC family in the C-terminal region and a unique regulatory region in the N-terminal region. PKN is activated by a small GTPase RhoA and unsaturated fatty acids such as arachidonic acid. The binding of both kinases and phophatases by the same scaffold protein provides a focal point where physiological events, such as cell cycle progression and intracellular membrane traffic, may be regulated by phosphorylation state of specific protein substrates. There are at least 4 isoforms of AKAP350 which lead to the possibility that they may behave differently at different subcellular locations. MAP2 is a member of a group of proteins that provide microtubule stabilization. MAP2 affinity appears to be dependent on PKA phosphorylation of MAP2. Pericentrin is also an AKAP (Diviani and Scott). Pericentrin binds Dynein which is also regulated by PKA leading to the possibility that pericentrin positions PKA to regulate dynein function (Diviani and Scott). Another example of AKAP/PKA interaction is illustrated in the AKAP95 role in mitosis and chromosome dynamics pathway. More...

RHOA related Reactome pathways (count: 13)

ID	Name	Description
Gene mapped Reactome pathways
REACT_11051	rho gtpase_cycle	The cycling of Rho GTPases is tightly controlled by three cl...... The cycling of Rho GTPases is tightly controlled by three classes of protein. These are. More...
REACT_12464	pi3k akt_signalling	PI3K/AKT signalling is a major regulator of neuron survival....... PI3K/AKT signalling is a major regulator of neuron survival. It blocks cell death by both impinging on the cytoplasmic cell death machinery and by regulating the expression of genes involved in cell death and survival. In addition, it may also use metabolic pathways to regulate cell survival.The PI3K/AKT pathway also affects axon diameter and branching and regulates small G proteins like RhoA , which control the behaviour of the F-actin cytoskeleton. Moreover, through its connection with the TOR pathway, it promotes translation of a subset of mRNAs. More...
REACT_19277	sema4d induced_cell_migration_and_growth_cone_collapse	Sema4D-mediated attraction of endothelial cells requires Rho...... Sema4D-mediated attraction of endothelial cells requires Rho, but not R-Ras, signaling. Sema4D-mediated plexinB1 activation activates Rho and its downstream effector ROCK. ROCK then phosphorylates MLC to induce actomyosin stress fiber contraction and to direct the assembly of focal adhesion complexes and integrin-mediated adhesion. More...
REACT_12056	trka signalling_from_the_plasma_membrane	Trk receptors signal from the plasma membrane and from intra...... Trk receptors signal from the plasma membrane and from intracellular membranes, particularly from early endosomes. Signalling from the plasma membrane is fast but transient; signalling from endosomes is slower but long lasting. Signalling from the plasma membrane is annotated here. TRK signalling leads to proliferation in some cell types and neuronal differentiation in others. Proliferation is the likely outcome of short term signalling, as observed following stimulation of EGFR (EGF receptor). Long term signalling via TRK receptors, instead, was clearly shown to be required for neuronal differentiation in response to neurotrophins. More...
REACT_11061	signalling by_ngf	Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles i...... Neurotrophins (NGF, BDNF, NT-3, NT-4/5) play pivotal roles in survival, differentiation, and plasticity of neurons in the peripheral and central nervous system. They are produced, and secreted in minute amounts, by a variety of tissues. They signal through two types of receptors: TRK tyrosine kinase receptors (TRKA, TRKB, TRKC), which specifically interact with the different neurotrophins, and p75NTR, which interacts with all neurotrophins. TRK receptors are reported in a variety of tissues in addition to neurons. p75NTRs are also widespread. Neurotrophins and their receptors are synthesized as several different splice variants, which differ in terms of their biological activities. The nerve growth factor (NGF) was the first growth factor to be identified and has served as a model for studying the mechanisms of action of neurotrophins and growth factors. The mechanisms by which NGF generates diverse cellular responses have been studied extensively in the rat pheochromocytoma cell line PC12. When exposed to NGF, PC12 cells exit the cell cycle and differentiate into sympathetic neuron-like cells. Current data show that signalling by the other neurotrophins is similar to NGF signalling. More...
REACT_18407	g alpha_12_13_signalling_events	The alpha subunits of G12 and 13 bind RhoGEFs (guanine nucle...... The alpha subunits of G12 and 13 bind RhoGEFs (guanine nucleotide exchange factors, which activate small G proteins) providing a path to Rho-mediated cytoskeletal responses that are likely involved in shape change in platelets. More...
REACT_19388	g protein_beta_gamma_signalling	The classical role of the G-protein beta/gamma dimer was bel...... The classical role of the G-protein beta/gamma dimer was believed to be the inactivation of the alpha subunit, Gbeta/gamma was viewed as a negative regulator of Galpha signalling. It is now known that Gbeta/gamma subunits can directly modulate many effectors, including some also regulated by G alpha. More...
REACT_13776	p75 ntr_receptor_mediated_signalling	Besides signalling through the tyrosine kinase receptors TRK...... Besides signalling through the tyrosine kinase receptors TRK A, B, and C, the mature neurotrophins NGF, BDNF, and NT3/4 signal through their common receptor p75NTR. NGF binding to p75NTR activates a number of downstream signalling events controlling survival, death, proliferation, and axonogenesis, according to the cellular context. p75NTR is devoid of enzymatic activity, and signals by recruiting other proteins to its own intracellular domain. p75 interacting proteins include NRIF, TRAF2, 4, and 6, NRAGE, necdin, SC1, NADE, RhoA, Rac, ARMS, RIP2, FAP and PLAIDD. Here we annotate only the proteins for which a clear involvement in p75NTR signalling was demonstrated. A peculiarity of p75NTR is the ability to bind the pro-neurotrophins proNGF and proBDNF. Proneurotrophins do not associate with TRK receptors, whereas they efficiently signal cell death by apoptosis through p75NTR. The biological action of neurotrophins is thus regulated by proteolytic cleavage, with proforms preferentially activating p75NTR, mediating apoptosis, and mature forms activating TRK receptors, to promote survival. Moreover, the two receptors are utilised to differentially modulate neuronal plasticity. For instance, proBDNF-p75NTR signalling facilitates LTD, long term depression, in the hippocampus , while BDNF-TRKB signalling promotes LTP (long term potentiation). Many biological observations indicate a functional interaction between p75NTR and TRKA signaling pathways. More...
REACT_19271	semaphorin interactions	Semaphorins are a large family of cell surface and secreted ...... Semaphorins are a large family of cell surface and secreted guidance molecules divided into eight classes on the basis of their structures. They all have an N-terminal conserved sema domain. Semaphorins signal through multimeric receptor complexes that include other proteins such as plexins and neuropilins. More...
REACT_19290	g beta_gamma_signalling_through_pi3kgamma	PI3K gamma (PI3KG) is a heterodimer consisting of a p110 cat...... PI3K gamma (PI3KG) is a heterodimer consisting of a p110 catalytic subunit associated with a regulatory p101 or p84 subunit. PI3KG is most highly expressed in neutrophils, where the p101 form predominates (approximately 95%). G beta:gamma recruits PI3KG to the plasma membrane, both activating PI3KG and providing access to its substrate PIP2, which is converted to PIP3. More...
REACT_19184	downstream events_in_gpcr_signaling	G protein-coupled receptors. The beta:gamma G-protein dimer ...... G protein-coupled receptors. The beta:gamma G-protein dimer is also involved in downstream signaling , and some receptors form part of metastable complexes of receptor and accessory proteins such as the arrestins. GPCRs are involved in many diverse signaling events , using a variety of pathways that include modulation of adenylyl cyclase, phospholipase C, the mitogen activated protein kinases (MAPKs), extracellular signal regulated kinase (ERK) c-Jun-NH2-terminal kinase (JNK) and p38 MAPK. More...
REACT_18266	axon guidance	Axon guidance / axon pathfinding is the process by which neu...... Axon guidance / axon pathfinding is the process by which neurons send out axons to reach the correct targets. Growing axons have a highly motile structure at the growing tip called the growth cone, which senses the guidance cues in the environment through guidance cue receptors and responds by undergoing cytoskeletal changes that determine the direction of axon growth. Guidance cues present in the surrounding environment provide the necessary directional information for the trip. These extrinsic cues have been divided into attractive or repulsive signals that tell the growth cone where and where not to grow. Genetic and biochemical studies have led to the identification of highly conserved families of guidance molecules and their receptors that guide axons. These include netrins, Slits, semaphorins, and ephrins, and their cognate receptors, DCC and or uncoordinated-5 (UNC5), roundabouts (Robo), neuropilin and Eph. In addition, many other classes of adhesion molecules are also used by growth cones to navigate properly which include NCAM and L1CAM. More...
REACT_19259	sema4d in_semaphorin_signaling	Semaphorin 4D (Sema 4D/CD100) is an axon guidance molecule w...... Semaphorin 4D (Sema 4D/CD100) is an axon guidance molecule with two disulfide-linked 150-kDa subunits. SEMA4D is structurally defined by a conserved 500-amino acid extracellular domain with 16 cysteines (sema domain) and also an Ig-like domain C-terminal to the sema domain. Sema4D is expressed on the cell surface as a homodimer; cysteine 679 within the sema domain is required for this dimerization. The main receptors for Sema4D are plexin-B1 and CD72. The activation of plexins by semaphorins initiates a variety of signaling processes that involve several small GTPases of the Ras and Rho families. Sema4D-Plexin-B1 interaction appears to mediate different and sometimes opposite effects depending on the cellular context. Plexin-B1 activation inhibits integrin-mediated cell attachment and cell migration through the activation of the R-RasGAP activity inherent to plexin-B1 or through the inhibition of RhoA. However, activation of plexin-B1 by Sema4D stimulates the migration of endothelial cells by mediating the activation of RhoA. More...

RHOA related interactors from protein-protein interaction data in HPRD (count: 65)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
RHOA	PRKCA	No	in vivo	11284700
RHOA	TRPC1	No	in vitro;in vivo	12766172
RHOA	RHPN1	No	in vitro;in vivo	12221077
RHOA	DIAPH1	No	in vitro	16109481 , 15864301
RHOA	ARHGDIB	Yes	in vivo	9799233
RHOA	VAV2	No	in vivo	11909943
RHOA	ARHGEF18	No	in vitro	11085924
RHOA	DOCK7	No	in vitro	12432077
RHOA	SRGAP1	No	in vivo	11672528
RHOA	ARHGAP21	No	in vitro	15793564
RHOA	PRKCZ	No	in vivo	15210811
RHOA	ROCK1	No	in vitro;yeast 2-hybrid	8798490
RHOA	FLNA	No	in vivo	10051605
RHOA	PITPNM1	No	in vivo	15125835
RHOA	KCNA2	No	in vivo;yeast 2-hybrid	9635436
RHOA	ICMT	No	in vitro	9614111
RHOA	VAV1	No	in vivo	16397238
RHOA	SMURF1	No	in vitro;in vivo	16472676 , 15710384
RHOA	OPHN1	No	in vitro	11998687 , 9582072
RHOA	ARHGAP8	No	in vitro;in vivo	12944407
RHOA	ARHGDIG	No	in vitro	9113980
RHOA	RHOA	Yes	in vitro	15069594
RHOA	DAAM1	No	in vitro;in vivo	11779461
RHOA	TGFBR1	No	in vivo	15761153
RHOA	RABAC1	No	in vivo;yeast 2-hybrid	11335720
RHOA	ARHGEF11	No	in vitro	10526156 , 15530360
RHOA	RTKN	No	in vitro;yeast 2-hybrid	8662891 , 14506264
RHOA	RASGRF1	Yes	in vivo	10220378
RHOA	PKN1	No	in vitro;in vivo	9446575 , 8571127 , 10619026
RHOA	RHPN2	No	in vitro;in vivo	12221077
RHOA	SPRED2	No	in vivo	15184877
RHOA	MCF2L	No	in vitro	12006984
RHOA	DVL2	No	in vivo	12533515
RHOA	ARHGEF12	No	in vitro;in vivo	11373293
RHOA	RAP1GDS1	No	in vitro;yeast 2-hybrid	11948427
RHOA	ARHGEF3	No	in vivo	12221096
RHOA	ARHGEF4	No	in vitro	10947987
RHOA	ARHGAP1	No	in vitro	9548756
RHOA	ARHGDIA	No	in vitro;in vivo	10489445
RHOA	DGKQ	No	in vitro;in vivo	10066731
RHOA	MPRIP	No	in vitro;in vivo	14506264
RHOA	TRIO	Yes	in vitro	10948190
RHOA	ARHGAP5	No	in vitro	9407060
RHOA	CNTNAP1	No	in vitro	9407060
RHOA	ARHGEF2	Yes	in vitro	9857026
RHOA	SH3BP1	No	in vitro	9548756
RHOA	MCF2	No	in vitro	10854437
RHOA	TGM2	No	in vivo	11350930
RHOA	PPP1R12A	No	in vitro;in vivo	9354661
RHOA	HSPA1A	No	in vivo	12490434
RHOA	CIT	No	in vitro;yeast 2-hybrid	8543060
RHOA	PLEKHG2	No	in vitro	11839748
RHOA	DEF6	No	in vitro	15023524
RHOA	CNKSR1	Yes	in vitro;in vivo;yeast 2-hybrid	14749388 , 15670823
RHOA	GMIP	Yes	in vitro;in vivo	12093360
RHOA	PDE6D	No	in vivo;yeast 2-hybrid	11786539
RHOA	ITPR1	Yes	in vitro;in vivo	12766172
RHOA	PLCG1	No	in vitro;in vivo	12071848
RHOA	PKN2	No	in vitro;in vivo	8910519 , 9121475
RHOA	KTN1	No	in vitro;in vivo;yeast 2-hybrid	8769096 , 11689693
RHOA	AKAP13	No	in vivo	12423633 , 11696353
RHOA	PRKACA	No	in vitro;in vivo	12654918
RHOA	VAV3	No	in vitro	10523675
RHOA	CAV1	No	in vitro	9647788
RHOA	PLD1	No	in vitro;in vivo	11311142 , 12593858 , 9565577

Gene Report

Literature-origin GO terms

Gene mapped GO terms

Literature-origin KEGG pathway

Gene mapped KEGG pathways

Gene mapped BioCarta pathways

Gene mapped Reactome pathways