Gene Report

Basic Information

Approved Symbol	EGF
Approved Name	epidermal growth factor
Previous Name	epidermal growth factor (beta-urogastrone)
Location	4q25
Position	chr4:110834040-110934118 (+)
External Links	Entrez Gene: 1950 Ensembl: ENSG00000138798 UCSC: uc003hzy.4 HGNC ID: 3229
No. of Studies (Positive/Negative)	1(0/1)
Type	Literature-origin; SNP mapped; Protein mapped

Positive relationships between EGF and MDD (count: 0)

Positive relationships between EGF and other components at different levels (count: 0)

Positive relationship network of EGF 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 EGF and MDD (count: 1)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
EGF	Tian W, 2012	patients and normal controls		None of the informative SNPs showed an allelic association w...... None of the informative SNPs showed an allelic association with MDD More...

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

EGF related SNPs in MK4MDD (count: 2)

#rs	Location	Annotation	No. of Studies (Positive/Negative)
rs11569017	chr4:110902111(Forward)	downstream_gene_variant; missense_variant; nc_transcript_variant; non_coding_exon_variant	1(1/0)
rs11569126	chr4:110929653(Forward)	intron_variant; nc_transcript_variant	1(1/0)

EGF related proteins in MK4MDD (count: 1)

Approved Name	UniportKB	No. of Studies (Positive/Negative)	Source
Pro-epidermal growth factor	P01133	1(1/0)	Literature-origin

EGF related GO terms (count: 41)

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0035413	positive regulation of catenin import into nucleus	biological process	IDA
GO:0045893	positive regulation of transcription, DNA-dependent	biological process	IDA[16314496]
GO:0045840	positive regulation of mitosis	biological process	IDA[15611079]
GO:0001525	angiogenesis	biological process	IDA[15611079]
GO:0008284	positive regulation of cell proliferation	biological process	IDA
GO:0018108	peptidyl-tyrosine phosphorylation	biological process	IEA
GO:0030168	platelet activation	biological process	TAS
GO:0045741	positive regulation of epidermal growth factor-activated receptor activity	biological process	IDA[15611079]; TAS[9712850]
GO:0070371	ERK1 and ERK2 cascade	biological process	IDA[16314496]
GO:0006260	DNA replication	biological process	TAS[9482941]
GO:2000008	regulation of protein localization to cell surface	biological process	IDA[19996314]
GO:0005576	extracellular region	cellular component	IC[9712850]; TAS
GO:0051048	negative regulation of secretion	biological process	IDA[10559227]
GO:0005886	plasma membrane	cellular component	IEA
GO:0005515	protein binding	molecular function	IPI[12620237]
GO:0008083	growth factor activity	molecular function	IDA[15611079]
GO:2000060	positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process	biological process	IEA
GO:0043406	positive regulation of MAP kinase activity	biological process	IDA[15611079]
GO:0042327	positive regulation of phosphorylation	biological process	IDA[15611079]
GO:0007596	blood coagulation	biological process	TAS
GO:0007262	STAT protein import into nucleus	biological process	ISS
GO:0000186	activation of MAPKK activity	biological process	IEA
GO:0031093	platelet alpha granule lumen	cellular component	TAS
GO:0030297	transmembrane receptor protein tyrosine kinase activator activity	molecular function	TAS[9712850]
GO:0005509	calcium ion binding	molecular function	IEA
GO:0010800	positive regulation of peptidyl-threonine phosphorylation	biological process	IDA[16314496]
GO:1900127	positive regulation of hyaluronan biosynthetic process	biological process	IDA[17324121]
GO:0042059	negative regulation of epidermal growth factor receptor signaling pathway	biological process	TAS
GO:0007165	signal transduction	biological process	TAS
GO:0021940	positive regulation of cerebellar granule cell precursor proliferation	biological process	IEA
GO:0060749	mammary gland alveolus development	biological process	IEA
GO:0005615	extracellular space	cellular component	IEA
GO:0007173	epidermal growth factor receptor signaling pathway	biological process	TAS
GO:0043388	positive regulation of DNA binding	biological process	ISS
GO:0002576	platelet degranulation	biological process	TAS
GO:0048754	branching morphogenesis of a tube	biological process	IEA
GO:0016021	integral to membrane	cellular component	IEA
GO:0005154	epidermal growth factor receptor binding	molecular function	TAS[15611079]
GO:0090370	negative regulation of cholesterol efflux	biological process	IEA
GO:0007171	activation of transmembrane receptor protein tyrosine kinase activity	biological process	TAS[9712850]
GO:0090279	regulation of calcium ion import	biological process	IDA[19996314]

EGF related KEGG pathways (count: 15)

ID	Name	Brief Description	Full Description
Literature-origin KEGG pathway
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
hsa04010	mapk signaling_pathway	MAPK signaling pathway	The mitogen-activated protein kinase (MAPK) cascade is a hig...... The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli. More...
hsa05213	endometrial cancer	Endometrial cancer	Two types of endometrial carcinoma are distinguished with re...... Two types of endometrial carcinoma are distinguished with respect to biology and clinical course. Type-I carcinoma is related to hyperestrogenism by association with endometrial hyperplasia, frequent expression of estrogen and progesterone receptors and younger age, whereas type-II carcinoma is unrelated to estrogen, associated with atrophic endometrium, frequent lack of estrogen and progesterone receptors and older age. This classification has also been justified at the molecular level with Type 1 tumours being more commonly associated with abnormalities of DNA-mismatch repair genes, K-ras, PTEN and beta-catenin, and Type 2 tumours with abnormalities of p53 and HER2/neu. More...
hsa05219	bladder cancer	Bladder cancer	Bladder cancer arise and progress along two distinctive path...... Bladder cancer arise and progress along two distinctive pathways. The first of these is often preceded by simple and papillary hyperplasia and exhibits a tumour morphology that is low-grade, superficial and papillary. Papillary carcinoma has a tendency to recur locally, but rarely invades and metastasizes. These tumors frequently show a constitutive activation of the receptor tyrosine kinase-Ras pathway, exhibiting activating mutations in the HRAS and fibroblast growth factor receptor 3 (FGFR3) genes. The second tumour pathway is characterized by high-grade muscle-invasive tumours, which either originate from flat carcinoma in situ (CIS)/severe dysplasia or arise de novo. Over half of these tumours show defects in the tumour suppressors p53 and/or the retinoblastoma protein (RB) genes and pathways, and over 50% of these tumours progress to local and distant metastases. Some of the cell cycle-related molecules show evidence of epigenetic modulation through aberrant promoter hypermethylation in invasive bladder cancer. Invasion and metastases are promoted by several factors that alter the tumour microenvironment, including the aberrant expression of E-cadherins (E-cad), matrix metalloproteinases (MMPs), angiogenic factors such as vascular endothelial growth factor (VEGF). More...
hsa05212	pancreatic cancer	Pancreatic cancer	Normal duct epithelium progresses to infiltrating cancer thr...... Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Pancreatic ductal adenocarcinoma (PDA) show elevated expression of EGF receptors (e.g. HER2/neu) and their ligands (e.g.TGF-alpha) consistent with the presence of this autocrine loop. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway. More...
hsa05214	glioma	Glioma	Glioblastoma multiforme (GBM) formation is either de novo (p...... Glioblastoma multiforme (GBM) formation is either de novo (primary GBMs) or due to the progression of a lower grade glioma to a higher grade one through the acquisition of additional mutations (secondary GBMs). In primary GBM, disruption of the p53 pathway often occurs through loss of ARF, or less frequently through amplification of MDM2. Disruption of the RB pathway occurs through loss of INK4A. Amplification and/or mutation of the epidermal growth factor receptor (EGFR) is the most frequently detected genetic defect that is associated with primary GBM. In secondary GBM, loss of p53 and activation of the growth-factorreceptor-tyrosine-kinase signalling pathway (such as through overexpression of PDGF/PDGFR ) initiates tumour formation,whereas disruption of the retinoblastoma (RB) pathway contributes to the progression of tumour development. Loss of PTEN has been implicated in both pathways, although it is much more common in the pathogenesis of primary GBM. More...
hsa04540	gap junction	Gap junction	Gap junctions contain intercellular channels that allow dire...... Gap junctions contain intercellular channels that allow direct communication between the cytosolic compartments of adjacent cells. Each gap junction channel is formed by docking of two 'hemichannels', each containing six connexins, contributed by each neighboring cell. These channels permit the direct transfer of small molecules including ions, amino acids, nucleotides, second messengers and other metabolites between adjacent cells. Gap junctional communication is essential for many physiological events, including embryonic development, electrical coupling, metabolic transport, apoptosis, and tissue homeostasis. Communication through Gap Junction is sensitive to a variety of stimuli, including changes in the level of intracellular Ca2+, pH, transjunctional applied voltage and phosphorylation/dephosphorylation processes. This figure represents the possible activation routes of different protein kinases involved in Cx43 and Cx36 phosphorylation. More...
hsa04144	endocytosis	Endocytosis	Endocytosis is a mechanism for cells to remove ligands, nutr...... Endocytosis is a mechanism for cells to remove ligands, nutrients, and plasma membrane (PM) proteins, and lipids from the cell surface, bringing them into the cell interior. Transmembrane proteins entering through clathrin-dependent endocytosis (CDE) have sequences in their cytoplasmic domains that bind to the APs (adaptor-related protein complexes) and enable their rapid removal from the PM. In addition to APs and clathrin, there are numerous accessory proteins including dynamin. Depending on the various proteins that enter the endosome membrane, these cargoes are sorted to distinct destinations. Some cargoes, such as nutrient receptors, are recycled back to the PM. Ubiquitylated membrane proteins, such as activated growth-factor receptors, are sorted into intraluminal vesicles and eventually end up in the lysosome lumen via multivesicular endosomes (MVEs). There are distinct mechanisms of clathrin-independent endocytosis (CIE) depending upon the cargo and the cell type. More...
hsa04060	cytokine cytokine_receptor_interaction	Cytokine-cytokine receptor interaction	Cytokines are soluble extracellular proteins or glycoprotein...... Cytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell growth, differentiation, cell death, angiogenesis, and development and repair processes aimed at the restoration of homeostasis. Cytokines are released by various cells in the body, usually in response to an activating stimulus, and they induce responses through binding to specific receptors on the cell surface of target cells. Cytokines can be grouped by structure into different families and their receptors can likewise be grouped. More...
hsa05215	prostate cancer	Prostate cancer	The identification of key molecular alterations in prostate-...... The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes that catalyze conjunction of glutathione with harmful, electrophilic molecules, thereby protecting cells from carcinogenic factors. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by such carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. After therapeutic reduction in the levels of testosterone and dihydrotestosterone, the emergence of androgen-independent prostate cancer has been associated with mutations in the androgen receptor (AR) that permit receptor activation by other ligands, increased expression of androgen receptors accompanying AR amplification, and ligand-independent androgen-receptor activation. More...
hsa05200	pathways in_cancer	Pathways in cancer
hsa04012	erbb signaling_pathway	ErbB signaling pathway	The ErbB family of receptor tyrosine kinases (RTKs) couples ...... The ErbB family of receptor tyrosine kinases (RTKs) couples binding of extracellular growth factor ligands to intracellular signaling pathways regulating diverse biologic responses, including proliferation, differentiation, cell motility, and survival. Ligand binding to the four closely related members of this RTK family -epidermal growth factor receptor (EGFR, also known as ErbB-1 or HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4)-induces the formation of receptor homo- and heterodimers and the activation of the intrinsic kinase domain, resulting in phosphorylation on specific tyrosine residues (pY) within the cytoplasmic tail. Signaling effectors containing binding pockets for pY-containing peptides are recruited to activated receptors and induce the various signaling pathways. The Shc- and/or Grb2-activated mitogen-activated protein kinase (MAPK) pathway is a common target downstream of all ErbB receptors. Similarly, the phosphatidylinositol-3-kinase (PI-3K) pathway is directly or indirectly activated by most ErbBs. Several cytoplasmic docking proteins appear to be recruited by specific ErbB receptors and less exploited by others. These include the adaptors Crk, Nck, the phospholipase C gamma (PLCgamma), the intracellular tyrosine kinase Src, or the Cbl E3 ubiquitin protein ligase. More...
hsa05223	non small_cell_lung_cancer	Non-small cell lung cancer	Non-small-cell lung cancer (NSCLC) accounts for approximatel...... Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS and c-erbB-2, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Overexpression of c-erbB-2 or EGFR leads to a proliferative advantage. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector.Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect. More...
hsa05218	melanoma	Melanoma	Five distinct stages have been proposed in the evolution of ...... Five distinct stages have been proposed in the evolution of melanoma on the basis of histological criteria: common acquired and congenital nevi without dysplastic changes; dysplastic nevi with structural and architectural atypia; radial-growth phase (RGP) melanoma; vertical-growth phase (VGP) melanoma; and metastatic melanoma. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Moreover, melanoma development is strongly associated with inactivation of the p16INK4a/CDK4,6/pRb and p14ARF/HMD2/p53 tumor suppressor pathways. The vertical-growth phase and metastatic melanoma are notable for striking changes in the control of cell adhesion. Recently, amplification of the MITF gene was demonstrated in 10% of primary melanomas and 20% of metastatic melanomas, suggesting that MITF is a melanoma oncogene. More...

EGF related BioCarta pathways (count: 7)

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
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...
CBL_PATHWAY	cbl pathway	CBL mediated ligand-induced downregulation of EGF receptors	As with many cell-surface receptors, activation of the EGF r...... As with many cell-surface receptors, activation of the EGF receptor can result in receptor internalization through receptor-mediated endocytosis, desensitizing further receptor signaling. This process requires clathrin and occurs in clathrin-coated pits, which pinch off from the plasma membrane to form vesicles that move to the early endosome. From the early endosome, receptors can either be recycled back to the cell surface, or they can move through the late endosome to the lysosome for proteolytic degradation. The sorting of receptors in the early endosome for degradation requires the tyrosine kinase activity of activated growth factor receptor, and involves ubiquitination of the receptor. Targeting of receptors for degradation requires members of the Cbl gene family. Cbl proteins bind to tyrosine phosphorylated EGF receptor, and are E3 ubiquitination ligases that label receptor for degradation. Cbl also recruits Cin85 to the receptor complex, and blocking Cin85 interaction blocks receptor internalization and degradation. Endophilins are also a member of this receptor-bound protein complex. In its role as a ubiquitin ligase and docking protein, Cbl desensitizes EGF signaling and also opposes cellular proliferation induced by EGF. EGF activation also appears to activate the tyrosine kinase Src, which phosphorylates Cbl, and helps to activate the ubiquitination and degradation of EGF receptor. PKC activation and threonine phosphorylation of the EGF receptor can induce heterologous receptor internalization, but opposes Cbl-mediated receptor degradation. PKC phosphorylated receptors are sorted for recycling to the cell surface, and directed away from the late endosome and proteosome. Other growth factor receptors are regulated in a similar manner, including the PDGF receptor, HGF receptor and the CSF-1 receptor, indicating that this is a fairly general regulatory mechanism. The importance of Cbl in the down-regulation of growth factor signaling means that it will have an important role in cellular transformation and the development and treatment of cancer. More...
SPRY_PATHWAY	spry pathway	Sprouty regulation of tyrosine kinase signals	Four different members of the Sprouty protein family block t...... Four different members of the Sprouty protein family block the cellular proliferation and differentiation induced by several different growth factors, including EGF and FGF. One mechanism by which Sprouty proteins inhibit signaling is through binding to Grb-2, a signaling intermediary between the tyrosine kinase growth factors and the Ras/map kinase pathway. Binding of Sprouty to Grb-2 prevents Grb-2 and Sos-1 from interacting with downstream signaling factors that activate Ras and map kinases, including Ras, Raf-1, Mek1, Erk1/2 and downstream transcription factors. The action of Sprouty as an inhibitor of this pathway requires Sprouty phosphorylation and membrane localization, at the site of the factors it interacts with. The inhibition of growth factor signaling by Sprouty is specific to the Ras pathway since the PI3 Kinase pathway responsible for cell survival signals from growth factor receptors is not inhibited by Sprouty. Tyrosine kinase activity of growth factor receptors is also not affected. The mechanism by which Sprouty inhibits Ras activation may be by blocking the nucleotide exchange activity of Sos. Sprouty expression is induced by growth factor receptor activation of Ras signaling, provided a self-regulatory feedback inhibition mechanism that regulates growth factor signaling through Ras. In addition to blocking the Ras pathway, Sprouty also induces protein tyrosine phosphatase 1B activity. Activation of PTP1B by Sprouty is responsible for the inhibition of cellular migration that Sprouty causes, but is not involved in regulation of cellular proliferation. While blocking receptor tyrosine kinase signaling, at least one member of the Sprouty family, Sprouty-2, also acts by one mechanism to stimulate EGF receptor signaling. Cbl targets the EGF receptor for tagging with ubiquitin and proteolytic destruction. Sprouty-2 binds to Cbl and blocks the ubiquitination and destruction of the EGF receptor, increasing EGF signaling. More...
MCALPAIN_PATHWAY	mcalpain pathway	mCalpain and friends in Cell motility	The mammalian calpain gene family currently contains 13 dist...... The mammalian calpain gene family currently 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 ) One of the most carefully studied functions of the calpains is the regulation of integrin-mediated cell migration. Calpains digests the links between the actin cytoskeleton and several focal adhesion complex proteins; talin, paxillin and focal adhesion kinase. The release from the focal adhesion complex facilitates migration. Calpestatin is an inhibitor expressed in most cells. Calpestatin binds the four inhibitory domains of calpain. Release from calpestatin does not activate calpain. Activation requires additional signaling, coactivators and an appropriate calcium concentration. During cell migration calpain1 (mu-calpain) acts at the leading edge as a response to integrin signals or calcium fluxuations due to the stretch activated calcium channels. Calpain1 cleaves the target proteins, talin, exzrin, paxillin and the cytoplasmic tail of the integrins B1(a) and B3(b) to release the adhesion and form new adhesions. Calpain2 (M-calpain) is believed to be membrane bound and functions at the trailing edge of the migrating cell to cleave the integrins in response to growth factor receptor signals. PKA functions to down regulate or inhibit calpain2. Disease related notes: In Alzheimers disease, amyloid peptides interfere with calpain activity causing a mislocalization of cdk5. Deregulated cdk5 hyperphosphorylates tau promoting cell death in neurons. Mutations in the muscle specific calpain p94 lead to Limb Girdle muscular dystrophy 2A (LGMD2A). Over activity of calpains due to elevated calcium leads to tissue damage in the heart and brain More...
EGF_PATHWAY	egf pathway	EGF Signaling Pathway	The epidermal growth factor (EGF) peptide induces cellular p...... The epidermal growth factor (EGF) peptide induces cellular proliferation through the EGF receptor, which has a tyrosine kinase cytoplasmic domain, a single transmembrane domain and an extracellular domain involved in EGF binding and receptor dimerization. Inhibitors of the EGF receptor are being pursued as potential cancer therapies and EGF may stimulate wound healing. Mutation of the EGF receptor has been associated with cancer in humans. The proliferative effects of EGF are signaled through several pathways. Binding of EGF results in EGF receptor dimerization, autophosphorylation of the receptor, and tyrosine phosphorylation of other proteins. The EGF receptor activates ras and the MAP kinase pathway, ultimately causing phosphorylation of transcription factors such as c-Fos to create AP-1 and ELK-1 that contribute to proliferation. Activation of STAT-1 and STAT-3 transcription factors by JAK kinases in response to EGF contributes to proliferative signaling. Phosphatidylinositol signaling and calcium release induced by EGF activate protein kinase C, another component of EGF signaling. Crosstalk of EGF signaling with other pathways make the EGF receptor a junction point between signaling systems. More...
EGFR_SMRTE_PATHWAY	egfr smrte_pathway	Map Kinase Inactivation of SMRT Corepressor	Corepressors are coregulators that interact with transcripti...... Corepressors are coregulators that interact with transcriptional silencers in a variety of pathways such as cell proliferation, differentiation and apoptosis. Abnormal corepressor-silencer interactions have been implicated in a variety of human disease pathways including several types of leukemia. The regulation of the SMRT corepressor via the p38 and Mek-1 Kinase pathway is shown in this diagram. The EFG receptor represents one mechanism by which SMRT function is inhibited by the tyrosine kinase signaling pathway. The MEKK1 and p38 pathways are activated by EGF resulting in cross-regulation of SMRT. The induction of SMRT phosphorylation by each pathway is shown, causing SMRT to unbind from the transcription factor complexes represented by RXR, RAR, T3R and PLZF. More...
KERATINOCYTE_PATHWAY	keratinocyte pathway	Keratinocyte Differentiation	The epidermis, which provides a protective barrier that unde...... The epidermis, which provides a protective barrier that undergoes a constant renewal, is a multi-layered tissue with the proliferating cells located in the basal layer. As cells leave the basal layer the underog significant differentiation, biochemical and morphological remodeling. The final differentiation results in the formation of corneocytes. In vitro keratinocytes mimic this process. Several genes mark keratinocyte specific differentiation. Among the most frequently tracked markers are Transglutaminase, Cystatin and Involucrin. The keratinocyte differentiation studies have identified and provided significant detail regarding the involvement of three of the 4 major MAP kinase pathways from several diverse stimuli such as EGF, FAS, TNF and Calicium influx. The p38 cascade is represented twice since both p38alpha (p38) and p38delta (MAPK13) are involved. The keratinocyte differentiation cascased also provide for detailed study of the functions of individual PKC isoforms. It is interesting to note the contrasting functions of the PKC isoforms in this process. In recent studies it has been determined that the cPKC (conventional/classical Protein Kinase C) isoforms, which are calcium-, phospholipid-, and diacylglycerol-dependent are inhibitory where as the nPKC (novel Protein Kinase C) isoforms which are calcium independent are stimulatory for keratinocyte differentiation markers. On the right hand side is an earlier step showing the upregulation loop of TRAF2. This step occurs prior to the activation os ASK1 and the p38 cascade. More...

EGF related Reactome pathways (count: 8)

ID	Name	Description
Gene mapped Reactome pathways
REACT_318	platelet degranulation	Platelets function as exocytotic cells, secreting a plethora...... Platelets function as exocytotic cells, secreting a plethora of effector molecules at sites of vascular injury. Platelets contain a number of distinguishable storage granules including alpha granules, dense granules and lysosomes. On activation platelets release a variety of proteins, largely from storage granules but also as the result of apparent cell lysis. These act in an autocrine or paracrine fashion to modulate cell signaling. Alpha granules contain mainly polypeptides such as fibrinogen, von Willebrand factor, growth factors and protease inhibitors that that supplement thrombin generation at the site of injury. Dense granules contain small molecules, particularly adenosine diphosphate (ADP), adenosine triphosphate (ATP), serotonin and calcium, all recruit platelets to the site of injury. More...
REACT_12484	egfr downregulation	Regulation of receptor tyrosine kinase (RTK) activity is imp...... Regulation of receptor tyrosine kinase (RTK) activity is implicated in the control of almost all cellular functions. One of the best understood RTKs is epidermal growth factor receptor (EGFR). Growth factors can bind to EGFR and activate it to initiate signalling cascades within the cell. EGFRs can also be recruited to clathrin-coated pits which can be internalised into endocytic vesicles. From here, EGFRs can either be recycled back to the plasma membrane or directed to lysosomes for destruction.This provides a mechanism by which EGFR signalling is negatively regulated and controls the strength and duration of EGFR-induced signals. It also prevents EGFR hyperactivation as commonly seen in tumorigenesis. The proto-oncogene Cbl can negatively regulate EGFR signalling. The Cbl family of RING-type ubiquitin ligases are able to poly-ubiquitinate EGFR, an essential step in EGFR degradation. All Cbl proteins have a unique domain that recognises phosphorylated tyrosine residues on activated EGFRs. They also direct the ubiquitination and degradation of activated EGFRs by recruiting ubiquitin-conjugation enzymes. Cbl proteins function by specifically targeting activated EGFRs and mediating their down-regulation, thus providing a means by which signaling processes can be negatively regulated. Cbl also promotes receptor internalization via it's interaction with an adaptor protein, CIN85 (Cbl-interacting protein of 85kDa). CIN85 binds to Cbl via it's SH3 domain and is enhanced by the EGFR-induced tyrosine phosphorylation of Cbl. The proline-rich region of CIN85 interacts with endophilins which are regulatory components of clathrin-coated vesicles (CCVs). Endophilins bind to membranes and induce membrane curvature, in conjunction with other proteins involved in CCV formation. The rapid recruitment of endophilin to the activated receptor complex by CIN85 is the mechanism which controls receptor internalization. More...
REACT_12606	grb2 events_in_egfr_signaling	Autophosphorylation of tyrosine residues are docking sites f...... Autophosphorylation of tyrosine residues are docking sites for many downstream effectors in EGFR signaling. SH2-containing phosphotyrosine-binding domains of adaptor proteins like GRB2 is one such example. GRB2 is constitutively associated with SOS, a guanine nucleotide exchange factor of Ras. GRB2 binding to phosphorylated EGFR results in the recruitment of SOS to the plasma membrane where it comes in proximity to Ras. This mechanism has been seen to be the model for Ras activation. More...
REACT_798	platelet activation	Platelet activation begins with the initial binding of adhes...... Platelet activation begins with the initial binding of adhesive ligands and of the excitatory platelet agonists. Intracellular signaling reactions will then enhance the adhesive and procoagulant properties of tethered platelets or of platelets circulating in the proximity. From the subendothelial adhesive substrates, collagen and possibly vWF are the main inducers of platelet activation. GP VI is the most potent collagen receptor initiating signal generation, an ability derived from its interaction with the FcRI gamma chain. This results in the phosphorylation of the gamma-chain by the non-receptor tyrosine kinases of the Src family. The phosphotyrosine motif is recognized by the SH2 domains of Syk, a tyrosine kinase. This association activates the Syk enzyme, leading to activation. Four PARs are identified, of which PARs 1 ,3 and 4 are substrates for thrombin. PAR 1 is the predominant thrombin receptor, PAR 3 is minimally expressed and PAR 4 is less responsive to thrombin. Platelets do not store PAR1, due to limited protein synthesis, they are capable of responding to thrombin only once. Platelet activation further results in the scramblase-mediated transport of negatively-charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase complex (formed by the activated forms of the blood coagulation factors factor VIII and factor I). More...
REACT_604	hemostasis	Two principal mechanisms limit blood loss after vascular inj...... Two principal mechanisms limit blood loss after vascular injury. Initially, platelets are activated, adhere to the site of the injury, and aggregate into a plug that limits blood loss. Proteins and small molecules released from activated platelets stimulate the plug formation process, and fibrinogen from the plasma forms bridges between activated platelets. These events allow the initiation of the clotting cascade, the second mechanism to limit blood loss. Negatively charged phospholipids exposed on cell surfaces at the site of injury and on activated platelets interact with tissue factor, setting off a cascade of reactions leading to generation of fibrin and the formation of an insoluble fibrin clot that strengthens the platelet plug. More...
REACT_9417	signaling by_egfr	The epidermal growth factor receptor (EGFR) is one member of...... The epidermal growth factor receptor (EGFR) is one member of the ErbB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands leads to autophosphorylation of tyrosine residues on the receptor and subsequent activation of signal transduction pathways that are involved in regulating cellular proliferation, differentiation, and survival. Ligand binding with EGFR results in receptor homo- or heterodimerization at the cell surface. Trans-autophosphorylation of the EGFR tyrosine kinase domains occurs and the phosphorylated tyrosine kinase residues serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, such as Ras, which then stimulate an intracellular signal transduction cascade. More...
REACT_12578	gab1 signalosome	SHP2 down-regulates PI3K activation by dephosphorylating GAB...... SHP2 down-regulates PI3K activation by dephosphorylating GAB1. More...
REACT_20	formation of_platelet_plug	Hemostasis is a physiological response that culminates in th...... Hemostasis is a physiological response that culminates in the arrest of bleeding from an injured vessel. Acute vessel injury results in its constriction to reduce the loss of blood. Under normal conditions vascular endothelium supports vasodilation, inhibits platelet adhesion and activation, suppresses coagulation, enhances fibrin cleavage and is anti-inflammatory in character. Under acute vascular trauma vasoconstrictor mechanisms predominate and the endothelium becomes prothrombotic, procoagulatory and proinflammatory in nature. This is achieved by a reduction of endothelial dilating agents: adenosine, NO and prostacyclin; and the direct action of ADP, serotonin and thromboxane on vascular smooth muscle cells to elicit their contraction. The chief trigger for the change in endothelial function that leads to the formation of haemostatic thrombus is the loss of the endothelial cell barrier between blood and ECM components. Circulating platelets identify and discriminate areas of endothelial lesions; here, they adhere to the exposed sub endothelium. Their interaction with the various thrombogenic substrates and locally generated or released agonists results in platelet activation. This process is described as possessing two stages, firstly, adhesion - the initial tethering to a surface, and secondly aggregation - the platelet-platelet cohesion. More...

EGF related interactors from protein-protein interaction data in HPRD (count: 13)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
EGF	GRB2	No	in vivo	10973965
EGF	PIK3R2	No	in vivo	1334406
EGF	VTN	No	in vitro	11796824
EGF	ERBB2	No	in vitro	12093292
EGF	CPM	Yes	in vivo	7615511 , 8796265
EGF	DUSP3	No	in vitro	1281549
EGF	LMNA	No	in vitro;in vivo;yeast 2-hybrid	16248985
EGF	EGF	Yes	in vitro;in vivo;yeast 2-hybrid	9188692 , 11438527
EGF	ADAM12	No	in vivo	11786904
EGF	ERBB3	Yes	in vitro	12093292
EGF	NRG1	Yes	in vitro	7730382
EGF	ADRBK1	No	in vivo	15620700
EGF	EGFR	No	in vitro;in vivo	12093292 , 12620237 , 10788520 , 16274239 , 15620700 , 12297050

Gene Report

Gene mapped GO terms

Literature-origin KEGG pathway

Gene mapped KEGG pathways

Gene mapped BioCarta pathways

Gene mapped Reactome pathways