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FLASH GENE

Symbol

IRS1

contributors: mct - updated : 21-03-2017

HGNC name	insulin receptor substrate 1
HGNC id	6125

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	67.47 kb     2 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005544 2 - 8743 NP_005535 - 1242 - 1995 7499194

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine parathyroid       highly   thyroid       highly Nervous nerve       highly Urinary bladder       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose     moderately Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol   adipocyte

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	an N-terminal pleckstrin homology (PH) domain that can bind to the plasma membrane by interaction with phosphoinositides
	a phosphotyrosine-binding (PTB) domain recognizing phosphotyrosine in the amino acid sequence NPXpY, which is present in the juxtamembrane region of the autophosphorylated insulin receptor,
	several tyrosine phosphorylation sites in the C terminal region

HOMOLOGY

interspecies	homolog to rattus Irs1 (90.6 pc)
	homolog to murine Irs1 (90.5 pc)

Homologene

FAMILY

CATEGORY

signaling growth factor , receptor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic,microsome
	intracellular,nucleus
text	localization in proximity with the insulin receptor at the plasma membrane and caveolae has implications for insulin signaling in adipocytes

basic FUNCTION	mediating the biological response to insulin stimulation by binding and activating various enzymes or adaptor molecules
	may mediate the control of various cellular processes by insulin
	activating phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit
	critical mediator of the insulin/insulin-like growth factor 1 signaling, which is a proteolytic target of the CUL7 E3 ligase
	multisite docking protein positioned immediately downstream from the type I IGF and insulin receptors
	with IRS2, control the migratory response of breast cancer cells to IGF1 and may, therefore, be key molecules in determining breast cancer spread
	role for IRS1 in TGFB1-induced epithelial-mesenchymal transition in lung epithelial cells
	regulation of IRS1 expression level is critical for determining the differentiating capacity of mesenchymal stem cells (MSCs) and OS cells, and derangement of IRS1 levels can be a critical step in osteosarcoma (OS) transformation
	IRS1/2 promotes EMT and cell proliferation through stabilizing DVL2
	functions as a molecular scaffold to coordinate IGF1/IGFBP2 signaling during osteoblast differentiation
	new function of IRS1: that of maintaining cells in their normal, differentiated state
	new role for IRS1 as an endocytic regulator of IGFIR that ensures sustained IGF bioactivity, independent of its classic role as an adaptor in IGFIR signaling

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

carbohydrate

signaling

signal transduction

a component

INTERACTION

DNA

RNA

small molecule

protein	several proteins containing SH2 domains, such as PIK3s, GRB2 and with TNF, PTEN
	tyrosine phosphorylated in response to insulin stimulation
	binding to ROCK1
	is a critical mediator of the myogenic functions of raptor and RHEB
	KHDRBS1 interacts with IRS1 in basal conditions, and insulin increases the affinity between these two partners
	SQSTM1 participates in the insulin-signaling pathway through its interactions with IRS1
	MEMO1 binds to IRS1, activates the downstream PI3K/AKT1 signaling pathway, leads to upregulation of SNAI1 and thereby triggers the epithelial-mesenchymal transition (EMT) program
	CRTC2 can regulate insulin signaling at the level of insulin receptor substrate-1 (IRS1)
	CRTC2 negatively feeds back to IRS1 via control of FBXW8 stability and localization
	TNS2 is a novel protein tyrosine phosphatase (PTPase) of IRS1 that acts as a mediator to reduce IRS1 under a catabolic condition, resulting in muscle atrophy
	in addition to persistent MTOR signalling, increased CRTC2 signals can promote insulin resistance due to CRTC2-mediated degradation of IRS1
	TRIM72 is an ubiquitin E3 ligase that induces IRS1 ubiquitination with the help of an E2-conjugating enzyme, UBE2H
	APPL1 is a critical molecule that promotes IRS1/2-INSR interaction
	IRS1 is recruited to interact with the INSRR-catalyzed phospho-tyrosine CAV2, which facilitates IRS1 association with and activation by INSR to initiate IRS1-mediated downstream signaling
	PLIN2 inhibits insulin&
	8209;induced glucose uptake by activating NLRP3, CASP1 and IL1B, leading to a decreased IRS1 expression
	LPIN1 enhances the tumour-promoting function of insulin receptor substrate 1 (IRS1) by controlling IRS1 stability
	IRS1 modulates how long ligand-activated IGFIR remains at the cell surface before undergoing endocytosis in cell

cell & other

REGULATION

activated by

EIF2AK2 that up-regulates the inhibitory phosphorylation of IRS1 at Ser312

induced by

PTEN (augments insulin promoted tyrosine phosphorylation of IRS1)

repressed by

TNF (impairs insulin promoted tyrosine phosphorylation of IRS1)

ASSOCIATED DISORDERS

corresponding disease(s)

NIDDM3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral       loss of function enhances breast cancer metastasis and IRS1 has potentially metastasis suppressor functions for breast cancer constitutional     --low   in diabetes, IRS1 is down-regulated, and cells become resistant to insulin tumoral     --over   in breast cancer

Susceptibility

to type 2 or type 1 diabetes to polycystic ovary syndrome (PCOS) to high body mass index

Variant & Polymorphism SNP , other	polymorphism associated to susceptibility to obesity with insulin resistance and to type 1 diabetes (variant G972R)
	Gly972Arg polymorphism is associated with PCOS in the Japanese population
	C allele of rs2943641 is associated
	with increased T2D risk, fasting- and glucose-stimulated hyperinsulinemia and impaired insulin sensitivity
	body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and increased body mass index

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     new models to develop inhibitors against IRSs for anticancer therapy neurology acquired   IRS1 signaling is a therapeutic target for hypoxic brain injury in neonates

ANIMAL & CELL MODELS