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FLASH GENE

Symbol

IRS2

contributors: mct/npt/pgu - updated : 12-06-2015

HGNC name	insulin receptor substrate 2
HGNC id	6126

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	NIDDM3 diabetes mellitus, non insulin-dependent, 3
Location	13q34      Physical location : 110.406.185 - 110.438.914
Synonym symbol(s)	EVI86, IRS-2

DNA

TYPE	functioning gene
STRUCTURE	32.73 kb     2 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003749 2 - 7014 NP_003740 - 1338 - -

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 Digestive liver       highly Homo sapiens Endocrine adrenal gland       moderately   neuroendocrine pituitary     highly   pancreas       highly Homo sapiens Nervous nerve cranial nerve     highly Reproductive female system ovary     highly Urinary kidney       predominantly Homo sapiens Adult   kidney       predominantly Homo sapiens Fetal

tissue

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

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune lymphocyte Homo sapiens Adult Lymphoid/Immune macrophage Homo sapiens Adult Urinary epithelial cell Homo sapiens Adult Urinary epithelial cell Homo sapiens Fetal

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	pleckstrin-homology (PH) domain
	phosphotyrosine-binding (PTB) domain
	many potential tyrosine and serine/threonine phosphorylation sites
	a kinase regulatory-loop binding (KRLB) region

mono polymer

complex

HOMOLOGY

interspecies	homolog to rattus Irs2 (87.4 pc)
	homolog to murine Irs2 (87.1 pc)

intraspecies

homolog to IRS1

Homologene

FAMILY

IRS family

CATEGORY

protooncogene , signaling hormone growth factor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic,microsome

basic FUNCTION	pleiotropic mediator of insulin coordinating Igf-1 receptor-mediated beta cell development
	playing a role in insulin and cytokine signaling
	mediating the control of various cellular processes by insulin
	multisite docking protein positioned immediately downstream from the type I IGF and insulin receptors
	involved in the migratory response of breast cancer cells to IGFs
	with IRS1, control the migratory response of breast cancer cells to IGF1 and may, therefore, be key molecules in determining breast cancer spread
	acts as a negative regulator on memory formation by restricting dendritic spine generation
	novel roles for IRS2 and FOXO3 in the regulation of kidney epithelial cells by CDH1
	IRS2 signaling can modulate Huntington disease progression
	is essential for hearing
	IRS2 signalling is required for the proper development of spinal sensory neurons involved in the perception of pain
	expressed in the kidney epithelium and may play a role in the downstream protective events triggered by BMP7 in the kidney
	plays a critical role in testicular development, potentially by mediating IGF1 signalling during embryonic and early postnatal development
	IRS1/2 promotes EMT and cell proliferation through stabilizing DVL2
	IRS2 phosphorylation is cell cycle-regulated and PLK1 phosphorylation of IRS2 prevents premature mitotic exit via AKT1 inactivation

CELLULAR PROCESS	cell life, proliferation/growth

PHYSIOLOGICAL PROCESS

development

text	positive control of cell proliferation
	brain development

PATHWAY

metabolism

carbohydrate

signaling

signal transduction

glucose metabolism/IGF1 signaling cascade

a component

forming a complex with 14-3-3 protein (YWHA) in a baculovirus system

INTERACTION

DNA

RNA

small molecule

protein	insulin receptor
	PTPRN2 is involved in beta-cell growth via regulating stability of IRS2 protein by the molecular interaction with insulin receptor
	interacting with FOXO1 (reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling)
	alternative binding of ZNF1489 or SP1 to the described region in the IRS2 promoter regulates neuronal IRS2 expression in a PI3K-dependent manner
	EIF2AK2 regulates IRS2, in the liver, at the transcriptional rather than the posttranslational level, and this effect is mediated by the transcription factor, FOXO1
	TGFB1 signals via IRS2 in kidney epithelial cells
	MAPK10 protects beta-cells from apoptosis and dysfunction mainly through maintenance of a normal IRS2 to AKT2 signaling pathway
	CAMK4 regulates beta-cell proliferation and apoptosis in a CREB1-dependent manner and CAMK4-induced IRS2 expression is important in these processes
	IRS2 signalling is important for maintaining the activity of liver GCK
	APPL1 is a critical molecule that promotes IRS1/2-INSR interaction
	PLK1 is the responsible kinase for phosphorylation of IRS2 on two serine residues

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

NIDDM3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   in macrophages enhanced their accumulation in the vascular wall accompanied by increased expression of proinflammatory mediators in macrophages constitutional     --over   in the kidney tubules of diabetic nephropathy constitutional     --low   in Type 2 diabetics as well as in Alzheimer patients (

Susceptibility

polycystic ovary syndrome in non diabetic African-American women with th G/G genotype (G1057D) polymorphism morbid obesity with glucose intolerance

Variant & Polymorphism

Candidate gene
Marker	marker and/or mediator of diabetic nephropathy progression
Therapy target
	System Type Disorder Pubmed cancer     new models to develop inhibitors against IRSs for anticancer therapy neurology neurodegenerative huntington chorea decreasing IRS2 signaling could be part of a therapeutic approach to slow the progression of HD diabete metabolic syndrom   reduced IRS2-mediated insulin signal in macrophages is a potentially important therapeutic target to prevent the progression of atherosclerosis in patients with type 2 diabetes

ANIMAL & CELL MODELS

	irs2-/- mice
	chico-/-drosophila
	chronic hyperinsulinemia downregulates the mRNA for IRS2 in ob/ob mice
	female infertility caused by deletion of IRS2
	less Irs2 signaling in aging brains can promote healthy metabolism, attenuate meal-induced oxidative stress, and extend the life span of overweight and insulin-resistant mice
	Irs2-deficient mice show sensorineural hearing loss that is delayed by concomitant protein tyrosine phosphatase 1B (PTP1B) loss of function
	liver content of GCK was reduced in Irs2(-/-) mice as compared with controls, although GCKR levels were similar
	Irs2 (-/-) mice also exhibited reduced testicular size, suggesting that impairments in this model occur during development
	complete disruption of Irs2 in mice impairs long-term potentiation (LTP) of synaptic transmission in the hippocampus