Gene Report

Basic Information

Approved Symbol	INS
Approved Name	insulin
Location	11p15.5
Position	chr11:2181009-2182439 (-)
External Links	Entrez Gene: 3630 Ensembl: ENSG00000254647 HGNC ID: 6081
No. of Studies (Positive/Negative)	1(1/0)
Type	Literature-origin; Protein mapped

Positive relationships between INS and MDD (count: 1)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
insulin	Gaiteri, 2010	patients and normal controls	P-value<0.01	Biological networks and signal transduction pathways corresp...... Biological networks and signal transduction pathways corresponding to the identified gene set suggested putative dysregulated functions for several hormone-type factors previously implicated in depression (insulin, interleukin-1, thyroid hormone, estradiol and glucocorticoids; p<0.01 for association with depression-related networks). More...

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

Positive relationship network of INS in MK4MDD

Network loading ...

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 INS and MDD (count: 0)

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

INS related SNPs in MK4MDD (count: 0)

INS related proteins in MK4MDD (count: 1)

Approved Name	UniportKB	No. of Studies (Positive/Negative)	Source
Insulin	P01308	1(1/0)	Literature-origin

INS related GO terms (count: 71)

ID	Name	Type	Evidence
Literature-origin GO terms
GO:0000165	MAPK cascade	biological process	IDA[11278339]

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0051000	positive regulation of nitric-oxide synthase activity	biological process	NAS[12135947]
GO:0007267	cell-cell signaling	biological process	IC[7556975]
GO:0006112	energy reserve metabolic process	biological process	TAS
GO:0030307	positive regulation of cell growth	biological process	NAS[11742412]
GO:0032460	negative regulation of protein oligomerization	biological process	IDA[9830016]
GO:0045821	positive regulation of glycolysis	biological process	IDA[7688386]; IMP[381941]
GO:0005576	extracellular region	cellular component	IC[7556975]; TAS
GO:0045725	positive regulation of glycogen biosynthetic process	biological process	IDA[17925406]
GO:0008286	insulin receptor signaling pathway	biological process	TAS
GO:0008284	positive regulation of cell proliferation	biological process	IDA[17925406]
GO:0043066	negative regulation of apoptotic process	biological process	NAS[16604263]
GO:0050796	regulation of insulin secretion	biological process	TAS
GO:0050709	negative regulation of protein secretion	biological process	IDA[14739855]
GO:0042177	negative regulation of protein catabolic process	biological process	IDA[15185208]
GO:0060267	positive regulation of respiratory burst	biological process	IDA[9092559]
GO:0022898	regulation of transmembrane transporter activity	biological process	IDA[14615391]
GO:0055089	fatty acid homeostasis	biological process	IMP[1184755]
GO:0051897	positive regulation of protein kinase B signaling cascade	biological process	IDA[11500939]
GO:0002674	negative regulation of acute inflammatory response	biological process	IDA[11443198]
GO:0045922	negative regulation of fatty acid metabolic process	biological process	IMP[1184755]
GO:0033861	negative regulation of NAD(P)H oxidase activity	biological process	IDA[11443198]
GO:0007186	G-protein coupled receptor signaling pathway	biological process	IDA[9092559]
GO:0031018	endocrine pancreas development	biological process	TAS
GO:0060266	negative regulation of respiratory burst involved in inflammatory response	biological process	IDA[11443198]
GO:0090336	positive regulation of brown fat cell differentiation	biological process	TAS[11387233]
GO:0005158	insulin receptor binding	molecular function	IDA[9667398]; IPI[8452530]
GO:0046326	positive regulation of glucose import	biological process	IDA[14615391]
GO:0006953	acute-phase response	biological process	IDA[14739855]
GO:0005615	extracellular space	cellular component	IDA[9667398]
GO:0050731	positive regulation of peptidyl-tyrosine phosphorylation	biological process	IDA[11278339]
GO:0045721	negative regulation of gluconeogenesis	biological process	NAS[11742412]
GO:0044281	small molecule metabolic process	biological process	TAS
GO:0050708	regulation of protein secretion	biological process	IDA[15591776]
GO:0031904	endosome lumen	cellular component	TAS
GO:0005796	Golgi lumen	cellular component	TAS
GO:0032880	regulation of protein localization	biological process	IDA[14615391]
GO:0032148	activation of protein kinase B activity	biological process	IDA[8702995]
GO:0046889	positive regulation of lipid biosynthetic process	biological process	NAS[11742412]
GO:0046631	alpha-beta T cell activation	biological process	IDA[10604997]
GO:0005788	endoplasmic reticulum lumen	cellular component	TAS
GO:0030141	secretory granule	cellular component	TAS
GO:0006355	regulation of transcription, DNA-dependent	biological process	NAS[12881524]
GO:0045908	negative regulation of vasodilation	biological process	NAS[12946932]
GO:0002020	protease binding	molecular function	IPI
GO:0045861	negative regulation of proteolysis	biological process	IMP[3553851]
GO:0050715	positive regulation of cytokine secretion	biological process	IDA[15473891]
GO:0005179	hormone activity	molecular function	IC[9667398]; IMP[381941]; NAS[14986111]
GO:0045740	positive regulation of DNA replication	biological process	IDA[7688386]
GO:0032270	positive regulation of cellular protein metabolic process	biological process	IMP[3553851]
GO:0005159	insulin-like growth factor receptor binding	molecular function	IPI[8452530]
GO:0006521	regulation of cellular amino acid metabolic process	biological process	IMP[3553851]
GO:0015758	glucose transport	biological process	IDA[14615391]
GO:0050995	negative regulation of lipid catabolic process	biological process	NAS[11742412]
GO:0042593	glucose homeostasis	biological process	IMP[381941]
GO:0045818	negative regulation of glycogen catabolic process	biological process	IMP[381941]
GO:0042060	wound healing	biological process	IDA[9498508]
GO:0006006	glucose metabolic process	biological process	IEA
GO:0043410	positive regulation of MAPK cascade	biological process	IDA[11500939]
GO:0030335	positive regulation of cell migration	biological process	ISS[12138094]
GO:2000252	negative regulation of feeding behavior	biological process	IDA[17957153]
GO:0045597	positive regulation of cell differentiation	biological process	NAS[11742412]
GO:0046628	positive regulation of insulin receptor signaling pathway	biological process	IDA[7688386]
GO:0051092	positive regulation of NF-kappaB transcription factor activity	biological process	IDA[19727662]
GO:0045909	positive regulation of vasodilation	biological process	NAS[14744991]
GO:0090277	positive regulation of peptide hormone secretion	biological process	TAS[11387233]
GO:0031954	positive regulation of protein autophosphorylation	biological process	ISS[3518947]
GO:0014068	positive regulation of phosphatidylinositol 3-kinase cascade	biological process	IDA[7688386]
GO:0045429	positive regulation of nitric oxide biosynthetic process	biological process	NAS[14615391]
GO:0005515	protein binding	molecular function	IPI[9388210]
GO:0045840	positive regulation of mitosis	biological process	IDA[11500939]

INS related KEGG pathways (count: 11)

ID	Name	Brief Description	Full Description
Literature-origin KEGG pathway
hsa04150	mtor signaling_pathway	mTOR signaling pathway
hsa04940	type i_diabetes_mellitus	Type I diabetes mellitus	Type I diabetes mellitus is a disease that results from auto...... Type I diabetes mellitus is a disease that results from autoimmune destruction of the insulin-producing beta-cells. Certain beta-cell proteins act as autoantigens after being processed by antigen-presenting cell (APC), such as macrophages and dendritic cells, and presented in a complex with MHC-II molecules on the surface of the APC. Then immunogenic signals from APC activate CD4+ T cells, predominantly of the Th1 subset. Antigen-activated Th1 cells produce IL-2 and IFNgamma. They activate macrophages and cytotoxic CD8+ T cells, and these effector cells may kill islet beta-cells by one or both of two types of mechanisms: (1) direct interactions of antigen-specific cytotoxic T cells with a beta-cell autoantigen-MHC-I complex on the beta-cell, and (2) non-specific inflammatory mediators, such as free radicals/oxidants and cytokines (IL-1, TNFalpha, TNFbeta, IFNgamma). Type I diabetes is a polygenic disease. One of the principle determining genetic factors in diabetes incidence is the inheritance of mutant MHC-II alleles. Another plausible candidate gene is the insulin gene. More...
hsa04810	regulation of_actin_cytoskeleton	Regulation of actin cytoskeleton

ID	Name	Brief Description	Full Description
Gene mapped KEGG pathways
hsa04960	aldosterone regulated_sodium_reabsorption	Aldosterone-regulated sodium reabsorption	Sodium transport across the tight epithelia of Na+ reabsorbi...... Sodium transport across the tight epithelia of Na+ reabsorbing tissues such as the distal part of the kidney nephron and colon is the major factor determining total-body Na+ levels, and thus, long-term blood pressure. Aldosterone plays a major role in sodium and potassium metabolism by binding to epithelial mineralocorticoid receptors (MR) in the renal collecting duct cells localized in the distal nephron, promoting sodium resorption and potassium excretion. Aldosterone enters a target cell and binds MR, which translocates into the nucleus and regulates gene transcription. Activation of MR leads to increased expression of Sgk-1, which phosphorylates Nedd4-2, an ubiquitin-ligase which targets ENAC to proteosomal degradation. Phosphorylated Nedd4-2 dissociates from ENAC, increasing its apical membrane abundance. Activation of MR also leads to increased expression of Na+/K+-ATPase, thus causing a net increase in sodium uptake from the renal filtrate. The specificity of MR for aldosterone is provided by 11beta-HSD2 by the rapid conversion of cortisol to cortisone in renal cortical collecting duct cells. Recently, besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented. More...
hsa04950	maturity onset_diabetes_of_the_young	Maturity onset diabetes of the young	About 2-5% of type II diabetic patients suffer from a monoge...... About 2-5% of type II diabetic patients suffer from a monogenic disease with autosomal dominant inheritance. This monogenic form of type II diabetes is called maturity onset diabetes of the young (MODY). We now know that MODY is caused by heterozygous mutations in at least five genes encoding transcription factors: HNF4alpha (MODY1), HNF1alpha (MODY3), PDX1 (MODY4), HNF1beta (MODY5) and NEUROD1 (MODY6). MODY2, which is so far the only subtype not related to a transcription factor, is caused by mutations in the glucokinase gene. Mutations of MODY transcription factor genes lead to abnormal expression of genes involved in pancreatic islet development and metabolism. More...
hsa04140	regulation of_autophagy	Regulation of autophagy
hsa04910	insulin signaling_pathway	Insulin signaling pathway	Insulin binding to its receptor results in the tyrosine phos...... Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). This allows association of IRSs with the regulatory subunit of phosphoinositide 3-kinase (PI3K). PI3K activates 3-phosphoinositide-dependent protein kinase 1 (PDK1), which activates Akt, a serine kinase. Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. Activation of Akt also results in the translocation of GLUT4 vesicles from their intracellular pool to the plasma membrane, where they allow uptake of glucose into the cell. Akt also leads to mTOR-mediated activation of protein synthesis by eIF4 and p70S6K. The translocation of GLUT4 protein is also elicited through the CAP/Cbl/TC10 pathway, once Cbl is phosphorylated by INSR. Other signal transduction proteins interact with IRS including GRB2. GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. SHC is another substrate of INSR. When tyrosine phosphorylated, SHC associates with GRB2 and can thus activate the RAS/MAPK pathway independently of IRS-1. 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...
hsa04914	progesterone mediated_oocyte_maturation	Progesterone-mediated oocyte maturation	Xenopus oocytes are naturally arrested at G2 of meiosis I. E...... Xenopus oocytes are naturally arrested at G2 of meiosis I. Exposure to either insulin/IGF-1 or the steroid hormone progesterone breaks this arrest and induces resumption of the two meiotic division cycles and maturation of the oocyte into a mature, fertilizable egg. This process is termed oocyte maturation. The transition is accompanied by an increase in maturation promoting factor (MPF or Cdc2/cyclin B) which precedes germinal vesicle breakdown (GVBD). Most reports point towards the Mos-MEK1-ERK2 pathway and the polo-like kinase/CDC25 pathway as responsible for the activation of MPF in meiosis, most likely triggered by a decrease in cAMP. More...
hsa04114	oocyte meiosis	Oocyte meiosis	During meiosis, a single round of DNA replication is followe...... During meiosis, a single round of DNA replication is followed by two rounds of chromosome segregation, called meiosis I and meiosis II. At meiosis I, homologous chromosomes recombine and then segregate to opposite poles, while the sister chromatids segregate from each other at meoisis II. In vertebrates, immature oocytes are arrested at the PI (prophase of meiosis I). The resumption of meiosis is stimulated by progesterone, which carries the oocyte through two consecutive M-phases (MI and MII) to a second arrest at MII. The key activity driving meiotic progression is the MPF (maturation-promoting factor), a heterodimer of CDC2 (cell division cycle 2 kinase) and cyclin B. In PI-arrested oocytes, MPF is initially inactive and is activated by the dual-specificity CDC25C phosphatase as the result of new synthesis of Mos induced by progesterone. MPF activation mediates the transition from the PI arrest to MI. The subsequent decrease in MPF levels, required to exit from MI into interkinesis, is induced by a negative feedback loop, where CDC2 brings about the activation of the APC (anaphase-promoting complex), which mediates destruction of cyclin B. Re-activation of MPF for MII requires re-accumulation of high levels of cyclin B as well as the inactivation of the APC by newly synthesized Emi2 and other components of the CSF (cytostatic factor), such as cyclin E or high levels of Mos. CSF antagonizes the ubiquitin ligase activity of the APC, preventing cyclin B destruction and meiotic exit until fertilization occurs. Fertilization triggers a transient increase in cytosolic free Ca2+, which leads to CSF inactivation and cyclin B destruction through the APC. Then eggs are released from MII into the first embryonic cell cycle. More...
hsa04930	type ii_diabetes_mellitus	Type II diabetes mellitus	Insulin resistance is strongly associated with type II diabe...... Insulin resistance is strongly associated with type II diabetes. Diabetogenic factors including FFA, TNFalpha and cellular stress induce insulin resistance through inhibition of IRS1 functions. Serine/threonine phosphorylation, interaction with SOCS, regulation of the expression, modification of the cellular localization, and degradation represent the molecular mechanisms stimulated by them. Various kinases (ERK, JNK, IKKbeta, PKCzeta, PKCtheta and mTOR) are involved in this process. The development of type II diabetes requires impaired beta-cell function. Chronic hyperglycemia has been shown to induce multiple defects in beta-cells. Hyperglycemia has been proposed to lead to large amounts of reactive oxygen species (ROS) in beta-cells, with subsequent damage to cellular components including PDX-1. Loss of PDX-1, a critical regulator of insulin promoter activity, has also been proposed as an important mechanism leading to beta-cell dysfunction. Although there is little doubt as to the importance of genetic factors in type II diabetes, genetic analysis is difficult due to complex interaction among multiple susceptibility genes and between genetic and environmental factors. Genetic studies have therefore given very diverse results. Kir6.2 and IRS are two of the candidate genes. It is known that Kir6.2 and IRS play central roles in insulin secretion and insulin signal transmission, respectively. More...

INS related BioCarta pathways (count: 4)

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
GH_PATHWAY	gh pathway	Growth Hormone Signaling Pathway	Growth hormone plays a major role in regulating growth durin...... Growth hormone plays a major role in regulating growth during childhood and adolescence and also regulates metabolism. Defects in growth hormone signaling can result in dwarfism and decreases in growth hormone levels with age have been suggested to play a role in the reduced function of some physiological systems. Growth hormone signals a response in cells through the growth hormone receptor, a member of the cytokine receptor gene family. Growth hormone causes the receptor to dimerize, activating the JAK2 protein kinase. The activity of JAK2 mediates many of the downstream responses to growth hormone through phosphorylation of STAT transcription factors, MAP kinases, other kinase cascades and molecules involved in metabolism like IRS-1. Factors like SOCS and SHP-1 appear to play a role in the down regulation of signaling by growth hormone and cytokines. More...
PPARA_PATHWAY	ppara pathway	Mechanism of Gene Regulation by Peroxisome Proliferators via PPARa(alpha)	The most recognized mechanism by which peroxisome proliferat...... The most recognized mechanism by which peroxisome proliferators regulated gene expresssion is through a PPAR/RXR heterodimeric complex binding to a peroxisome proliferator-response element (PPRE) (classical mechanism). However, there are the possibility of several variations on this theme: 1). The peroxisome proliferator interacts with PPAR that preexists as a DNA complex with associated corepressors proteins. The interaction with ligand causes release of the corepressor and association with a coactivator, resulting in the classical mechanism. 2). The peroxisome proliferator interacts with PPAR as a soluble member of the nucleus. The binding of ligand results in RXR heterodimerization, DNA binding and coactivator recruitment. 3). In this scenario, PPAR exists in the cytosol, perhaps complexed to heat shock protein 90 and/or other chaperones. Binding of peroxisome proliferator causes a conformational change and translocation into the nucleus. Scenarios 4 and 5 require regulation of gene expression via non-classical mechanisms: 4). PPAR is capable of interacting with, and forming DNA binding heterodimers with, several nuclear receptors including the thyroid hormone receptor. The binding site for this non-RXR heterodimer need not be the classic DR-1 motif found in the PPRE. 5). PPAR may participate in the regulation of gene expression witout binding to DNA. By association with transcription factors such as c-jun or p65, PPAR diminishes the ability of AP1 or NFB to bind to their cognate DNA sequences, respectively. Also shown in this scheme are two means to modify the peroxisome proliferator response. Most importantly, growth factor signaling has a pronounced affect on PPAR via post-translational modification. PPAR is a phosphoprotein and its activity is affected by insulin. Several kinase pathways affects PPARa's activity, although the specific kinases and phosphorylation sites have not been conclusively determined. More...
HDAC_PATHWAY	hdac pathway	Control of skeletal myogenesis by HDAC and calcium/calmodulin-dependent kinase (CaMK)	The differentiation of muscle cells is transcriptionally reg...... The differentiation of muscle cells is transcriptionally regulated, in part by the myocyte enhancer factor-2, MEF2. During myogenesis MEF2 binds to MyoD and other basic helix-loop-helix factors to activate transcription of genes involved in muscle cell differentiation. Transcriptional activation by MEF2 is blocked by interaction with HDAC5 and other histone deacetylases. In undifferentiated myoblasts, HDAC5 is present in the nucleus where it binds to MEF2 to block activation of muscle genes. When activated by IGF-1 signaling, CaM kinase phosphorylates HDAC proteins, causing them to be exported from the nucleus, releasing the block on MEF2 transcriptional activation and allowing differentiation to proceed. Transcription cofactors also interact with MEF2 to contribute to gene regulation and myogenesis. The transcriptional regulator NFAT, for example, acts as a cofactor for MEF2 when calcium and calcineurin signaling activate it. There are four members of the Mef2 gene family, Mef2a-2d. Mef2a is expressed in brain, heart and skeletal muscle. Mef2c is involved in myogenesis in cardiac and skeletal muscle. Mef2d is widely expressed, and may be involved in the regulation of T cell function as well as muscle. Several factors regulate Mef2 transcription factors, including Map kinases and histone deacetylase (HDAC) enzymes. Mef2 is phosphorylated by p38 map kinase, and phosphorylation of Mef2c by p38 contributes to skeletal muscle differentiation. BMK-1 (also called Erk5) is another member of the Map kinase family that regulates the activity of Mef2 family members and is unique in that it appears itself to possess a transcriptional activation domain and act as a transcriptional coactivator. Mekk3 disruption prevented normal cardiovascular development in mice and appears to signal through p38 and Mef2c in normal cardiovascular development. More...
INSULIN_PATHWAY	insulin pathway	Insulin Signaling Pathway	The appropriate signaling through the insulin pathway is cri...... The appropriate signaling through the insulin pathway is critical for the regulation of glucose levels and the avoidance of diabetes. Insulin forms a complex with the Insulin Receptor (IR) and b chains to form the active signaling complex. Through recruitment of adaptor molecules and the activation of RAS, the activated IR can cause transcriptional activation. More...

INS related Reactome pathways (count: 16)

ID	Name	Description
Gene mapped Reactome pathways
REACT_18339	inhibition of_insulin_secretion_by_adrenaline_noradrenaline	The catecholamines adrenaline (epinephrine) and noradrenalin...... The catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) inhibit insulin secretion from pancreatic beta cells. Four effects are seen in the cells: 1. Inhibition of exocytosis of secretory granules, the major effect. 2. Opening of ATP-sensitive potassium channels (KATP channels) and repolarization of the cell. 3. Closing of L-type voltage-dependent calcium channels and inhibition of calcium influx. 4. Inhibition of adenylyl cyclase activity. The first event in adrenaline/noradrenaline signaling in beta cells is the binding of adrenaline or noradrenaline to alpha-2 adrenergic receptors, which are G-protein coupled receptors. Binding activates the alpha subunits in heterotrimeric Gi and Go complexes to exchange GDP for GTP, forming the active G alpha:GTP complex. Experiments using specific antibodies against the alpha subunits in mice show that Gi alpha-1, Gi alpha-2, and Go alpha-2 are responsible for adrenergic effects. The exact beta and gamma subunits of the heterotrimeric G-proteins are unknown. After activation by GTP, the heterotrimeric complex dissociates into the G alpha:GTP complex and the beta:gamma complex. The G alpha:GTP complex causes the inhibition of exocytosis by an unknown mechanism that involves protein acylation. This is responsible for most of the observed inhibition of insulin secretion. Additionally, the G alpha:GTP complex activates (opens) KATP channels, allowing the cell to repolarize. The beta:gamma complex inhibits (closes) voltage-dependent calcium channels, reducing the intracellular calcium concentration, and inhibits adenylyl cyclase, reducing the intracellular cAMP concentration. More...
REACT_15380	diabetes pathways
REACT_21272	downstream signaling_of_activated_fgfr	Signaling via FGFRs is mediated via direct recruitment of si...... Signaling via FGFRs is mediated via direct recruitment of signaling proteins that bind to tyrosine auto-phosphorylation sites on the activated receptor and via closely linked docking proteins that become tyrosine phosphorylated in response to FGF-stimulation and form a complex with additional complement of signaling proteins. The activation loop in the catalytic domain of FGFR maintains the PTK domain in an inactive or low activity state. The activation-loop of FGFR1, for instance, contains two tyrosine residues that must be autophosphorylated for maintaining the catalytic domain in an active state. In the autoinhibited configuration, a kinase invariant proline residue at the C-terminal end of the activation loop interferes with substrate binding while allowing access to ATP in the nucleotidebinding site. Iin addition to the catalytic PTK core, the cytoplasmic domain of FGFR contains several regulatory sequences. The juxtamembrane domain of FGFRs is considerably longer than that of other receptor tyrosine kinases. This region contains a highly conserved sequence that serves as a binding site for the phosphotyrosine binding (PTB) domain of FRS2. A variety of signaling proteins are phosphorylated in response to FGF stimulation, including Shc, phospholipase-C gamma and FRS2 leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape. More...
REACT_19375	regulation of_insulin_secretion_by_free_fatty_acids	Free fatty acids augment the glucose-triggered secretion of ...... Free fatty acids augment the glucose-triggered secretion of insulin. The augmentation is believed to be due to the additive effects of the activation of the free fatty acid receptor 1 (FFAR1 or GPR40) and the metabolism of free fatty acids within the pancreatic beta cell. This module describes each pathway. More...
REACT_16921	glucose regulation_of_insulin_secretion	Increased blood glucose levels from dietary carbohydrate nor...... Increased blood glucose levels from dietary carbohydrate normally trigger insulin release from the beta cells of the pancreas. Glucose catabolism in the beta cell is the transducer that links increased glucose levels to insulin release. Glucose uptake and glycolysis generate cytosolic pyruvate; pyruvate is transported to mitochondria and converted both to oxaloacetate which increases levels of TCA cycle intermediates, and to acetyl-CoA which is oxidized to CO2 via the TCA cycle. The rates of ATP synthesis and transport to the cytosol increase, plasma membrane ATP-sensitive inward rectifying potassium channels. Elevated calcium concentrations near the plasma membrane cause insulin secretion in two phases: an initial high rate within minutes of glucose stimulation and a slow, sustained release lasting longer than 30 minutes. In the initial phase, 50-100 insulin granules already docked at the membrane are exocytosed. Exocytosis is rendered calcium-dependent by Synaptotagmin V/IX, a calcium-binding membrane protein located in the membrane of the docked granule, although the exact action of Synapototagmin in response to calcium is unknown. Calcium also causes a translocation of reserve granules within the cell towards the plasma membrane for release in the second, sustained phase of secretion. Human cells contain L-type. More...
REACT_1505	integration of_energy_metabolism	Many hormones that affect individual physiological processes...... Many hormones that affect individual physiological processes including the regulation of appetite, absorption, transport, and oxidation of foodstuffs influence energy metabolism pathways. While insulin mediates the storage of excess nutrients, glucagon is involved in the mobilization of energy resources in response to low blood glucose levels, principally by stimulating hepatic glucose output. Small doses of glucagon are sufficient to induce significant glucose elevations. These hormone-driven regulatory pathways enable the body to sense and respond to changed amounts of nutrients in the blood and demands for energy. Glucagon and Insulin act through various metabolites and enzymes that target specific steps in metabolic pathways for sugar and fatty acids. The processes responsible for the long-term control of fat synthesis and short term control of glycolysis by key metabolic products and enzymes are annotated in this module as six specific pathways: Pathway 1. Glucagon signalling in metabolic pathways: In response to low blood glucose, pancreatic alpha-cells release glucagon. The binding of glucagon to its receptor results in increased cAMP synthesis, and Protein Kinase A - Copyright National Academy of Sciences, U.S.A.). More...
REACT_13819	regulation of_gene_expression_in_beta_cells	Two transcription factors, PDX1 and HNF1A, play key roles in...... Two transcription factors, PDX1 and HNF1A, play key roles in maintaining the gene expression pattern characteristic of mature beta cells in the endocrine pancreas. Targets of these regulatory molecules include genes encoding insulin, the GLUT2 glucose transporter, the liver-. More...
REACT_508	signal attenuation	Now with the complete receptor-ligand dissociation and subse...... Now with the complete receptor-ligand dissociation and subsequent degradation of insulin in the endosomal lumen, the endosomally associated protein tyrosine phosphatases (PTPs) complete the receptor dephosphorylation. So too are all the receptor substrates dephosphorylated leading to the collapse of the signalling complexes and signal attenuation. More...
REACT_15550	insulin synthesis_and_secretion	Synthesis of insulin-containing secretory granules can be de...... Synthesis of insulin-containing secretory granules can be described in 6 steps: transcription of preproinsulin genes, translation of preproinsulin mRNA with concomitant removal of the signal peptide, formation of intramolecular disulfide bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin to yield insulin, translocation of the granules across the cytosol to the plasma membrane. Transcription of the human insulin gene INS is activated by 4 important transcription factors: Pdx-1, MafA, Beta2/NeuroD1, and E47. The transcription factors interact with each other at the promoters of the insulin gene and act synergistically to promote transcription. Expression of the transcription factors is upregulated in response to glucose. The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is cleaved during translation to yield proinsulin. Evidence indicates that the preproinsulin mRNA is stabilized by glucose. Within the ER, three intramolecular disulfide bonds form between cysteine residues in the proinsulin. Formation of the bonds is the spontaneous result of the conformation of proinsulin and the oxidizing environment of the ER, which is maintained by Ero1-like alpha The cystine bonded proinsulin then moves via vesicles from the ER to the Golgi Complex. High concentrations of zinc are maintained in the Golgi by zinc transporters ZnT5, ZnT6, and ZnT7 and the proinsulin forms complexes with zinc and calcium. Proinsulin-zinc-calcium complexes bud in vesicles from the trans-Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules the endoproteases Prohormone Convertase 1/3 and Prohormone Convertase 2 cleave at two sites of the proinsulin and Carboxypeptidase E removes a further 4 amino acid residues to yield the cystine-bonded A and B chains of mature insulin and the C peptide, which will also be secreted with the insulin. The insulin-zinc-calcium complexes form insoluble crystals within the granule The insulin-containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin-1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network. A pancreatic beta cell contains about 10000 insulin granules of which about 1000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE-type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin-2/VAMP2 on the granule membrane. Exocytosis is a calcium-dependent process due to interaction of the calcium-binding membrane protein Synaptotagmin V/IX with the SNARE-type proteins. More...
REACT_13698	regulation of_beta_cell_development	The normal development of the pancreas during gestation has ...... The normal development of the pancreas during gestation has been intensively investigated over the past decade especially in the mouse. Studies of genetic defects associated with maturity onset diabetes of the young. During embryogenesis, committed epithelial cells from the early pancreatic buds differentiate into mature endocrine and exocrine cells. It is helpful to schematize this process into four consecutive cellular stages, to begin to describe the complex interplay of signal transduction pathways and transcriptional networks. The annotations here are by no means complete - factors in addition to the ones described here must be active, and even for the ones that are described, only key examples of their regulatory effects and interactions have been annotated. It is also important to realize that in the human, unlike the mouse, cells of the different stages can be present simultaneously in the developing pancreas and the linear representation of these developmental events shown here is an over-simplification of the actual developmental process. The first stage of this process involves the predifferentiated epithelial cells of the two pancreatic anlagen that arise from the definitive endoderm at approximately somite stages 11-15 and undergo budding from somite stages 20-22. This period corresponds to gestational days 8.75-9.5 in the mouse, and 26 in the human. Pancreatic buds subsequently coalesce to form a single primitive gland, while concomitantly a ductal tree lined by highly proliferative epithelial cells is formed. A subset of such epithelial cells is thought to differentiate into either endocrine or acinar exocrine cells. A third cellular stage is defined by the endocrine-committed progenitors that selectively express the basic helix-loop-helix transcription factor NEUROG3. NEUROG3 is known to activate a complex transcriptional network that is essential for the specification of endocrine cells. Many transcription factors that are activated by NEUROG3 are also involved in islet-subtype cellular specification and in subsequent stages of differentiation of endocrine cells. This transient cellular stage thus leads to the generation of all known pancreatic endocrine cells, including insulin-producing beta-cells, and glucagon-producing alpha cells, the final stage of this schematic developmental process. The diagram below summarizes interactions that take place between transcription factors and transcription factor target genes during these cellular stages, and shows cases where there is both functional evidence that a transcription factor is required for the target gene to be expressed, and biochemical evidence that this interaction is direct. We also describe instances where a signaling pathway is known to regulate a transcription factor gene in this process, even if the intervening signaling pathway is not fully understood. More...
REACT_762	irs related_events	IRS is one of the mediators of insulin signalling events. It...... IRS is one of the mediators of insulin signalling events. It is activated by phosphorylation and triggers a cascade of events involving PI3K, SOS, RAF and the MAP kinases. The proteins mentioned under IRS are examples of IRS family members acting as indicated. More family members are to be confirmed and added in the future. More...
REACT_18274	regulation of_insulin_secretion_by_glucagon_like_peptide_1	Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in th...... Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in the intestine in response to glucose and fatty acids. GLP-1 circulates to the beta cells of the pancreas where it binds a G-protein coupled receptor, GLP-1R, on the plasma membrane. The binding activates the heterotrimeric G-protein G(s), causing the alpha subunit of G(s) to exchange GDP for GTP and dissociate from the beta and gamma subunits. The activated G(s) alpha subunit interacts with Adenylyl Cyclase VIII (Adenylate Cyclase VIII, AC VIII) and activates AC VIII to produce cyclic AMP (cAMP). cAMP then has two effects: 1) cAMP activates Protein Kinase A (PKA), and 2) cAMP activates Epac1 and Epac2, two guanyl nucleotide exchange factors. Binding of cAMP to PKA causes the catalytic subunits of PKA to dissociate from the regulatory subunits and become an active kinase. PKA is known to enhance insulin secretion by closing ATP-sensitive potassium channels, closing voltage-gated potassium channels, releasing calcium from the endoplasmic reticulum, and affecting insulin secretory granules. The exact mechanisms for PKA's action are not fully known. After prolonged increases in cAMP, PKA translocates to the nucleus where it regulates the PDX-1 and CREB transcription factors, activating transcription of the insulin gene. cAMP produced by AC VIII also activates Epac1 and Epac2, which catalyze the exchange of GTP for GDP on G-proteins, notably Rap1A.. Rap1A regulates insulin secretory granules and is believed to activate the Raf/MEK/ERK mitogenic pathway leading to proliferation of beta cells. The Epac proteins also interact with RYR calcium channels on the endoplasmic reticulum, the SUR1 subunits of ATP-sensitive potassium channels, and the Piccolo:Rim2 calcium sensor at the plasma membrane. More...
REACT_999	shc related_events	SHC is one of the mediators of insulin signalling events. It...... SHC is one of the mediators of insulin signalling events. It is activated by phosphorylation and triggers a cascade of events involving SOS, RAF and the MAP kinases. More...
REACT_18325	regulation of_insulin_secretion	Pancreatic beta cells integrate signals from several metabol...... Pancreatic beta cells integrate signals from several metabolites and hormones to control the secretion of insulin. In general, glucose triggers insulin secretion while other factors can amplify or inhibit the amount of insulin secreted in response to glucose. Factors which increase insulin secretion include the incretin hormones Glucose-dependent insulinotropic polypeptide (GIP and glucagon-like peptide-1 (GLP-1), acetylcholine, and fatty acids. Factors which inhibit insulin secretion include adrenaline and noradrenaline. More...
REACT_18405	regulation of_insulin_secretion_by_acetylcholine	Acetylcholine released by parasympathetic nerve endings in t...... Acetylcholine released by parasympathetic nerve endings in the pancreas causes a potentiation of insulin release when glucose is present at concentrations greater than about 7 mM. Acetylcholine binds the Muscarinic Acetylcholine Receptor M3 on pancreatic beta cells. The binding has two effects: an increase in permeability of the cell to Na+ ions through an unknown mechanism, and the activation of Phospholipase C beta-1 through a heterotrimeric G protein, G(q). After acetylcholine binds the Muscarinic Acetycholine Receptor M3, the receptor activates the G protein Gq by causing the alpha subunit of Gq to exchange GDP for GTP. Activation of Gq in turn activates Phospholipase C beta-1. Phospholipase C beta-1 hydrolyzes the phosphodiester bond at the third position of phosphoinositol 4,5-bisphosphate, producing diacylglycerols (DAG) and inositol 1,4,5-trisphosphate. DAG remains in the cell membrane and causes Protein Kinase C alpha (PKC alpha) to translocate from the cytosol to the membrane. This results in the activation of PKC alpha which then phosphorylates target proteins on serine and threonine residues. One known target of PKC alpha is Myristoylated Alanine-rich C Kinase Substrate (MARCKS), which is believed to affect vesicle transport and may be responsible for the increased traffic of insulin granules seen in response to acetylcholine. Inositol trisphophate binds a receptor, the IP3 receptor, on calcium stores in the cell (probably the endoplasmic reticulum). The release of calcium into the cytosol stimulates the exocytosis of insulin granules. More...
REACT_21270	pi3k cascade	The ability of growth factors to protect from apoptosis is p...... The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals. More...

INS related interactors from protein-protein interaction data in HPRD (count: 17)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
INS	NOV	No	in vitro	10084601
INS	IDE	No	in vitro	11145591 , 17051221
INS	HLA-DQA2	No	in vitro	11376336
INS	CPE	No	in vivo	10966857 , 7477119
INS	CTSD	No	in vitro;in vivo	11779865
INS	LRP2	No	in vitro	9773776
INS	INS	Yes	in vivo	12021212
INS	IGF1R	No	in vivo	1851182
INS	RB1	No	in vitro;in vivo	10938588 , 7818556
INS	SYTL4	No	in vitro	10497219
INS	TXNDC17	No	in vitro	14607844
INS	INSR	No	in vivo	2550426
INS	GCK	No	in vitro	12101177
INS	CTSE	No	in vitro	1959628 , 195962
INS	HLA-DQB1	No	in vitro	11376336
INS	IGFBP7	Yes	in vitro	9388210
INS	CTSB	Yes	in vitro	6351842

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