The protein IRS1 acts as an interface between signaling proteins with Src homology-2 domains (SH2
proteins) and the receptors for insulin , IGF2 , growth hormone , several
interleukins (IL4, IL9, IL13), and other cytokines. It regulates gene expression and stimulates
mitogenesis and appears to mediate insulin/IGF1-stimulated glucose transport. Thus, the finding that survival of the
homozygous Irs1 knockout mouse with only mild resistance to hypertension was surprising. This dilemma was
provisionally resolved by the discovery by Sun et al. (1995) of a second IRS signaling protein in mouse. They purified
and cloned a likely candidate from mouse myeloid progenitor cells and, because of its resemblance to IRS1, they
designated it IRS2. Alignment of the sequences of IRS2 and IRS1 demonstrated a highly conserved N terminus
containing a pleckstrin-homology domain and a phosphotyrosine-binding (PTB) domain, and a poorly conserved C
terminus containing several tyrosine phosphorylation motifs. IRS2 is expressed in many cells, including tissues from the
homozygous IRS1 knockout mouse.
NCBI Summary:
This gene encodes the insulin receptor substrate 2, a cytoplasmic signaling molecule that mediates effects of insulin, insulin-like growth factor 1, and other cytokines by acting as a molecular adaptor between diverse receptor tyrosine kinases and downstream effectors. The product of this gene is phosphorylated by the insulin receptor tyrosine kinase upon receptor stimulation, as well as by an interleukin 4 receptor-associated kinase in response to IL4 treatment. [provided by RefSeq, Jul 2008]
Wu XK et al 2000 evaluated the role of insulin-receptor substrate (IRS)-1 and -2
in ovary dysfunction in women with insulin resistance.
Sections of ovary were obtained at the time of cesarean section
from five volunteers without medical complications and three patients with
gestational diabetes mellitus. Immunoblotting with specific monoclonal and polyclonal antibodies
showed the presence of 165-kDa and 183-kDa proteins that corresponded to the
size of IRS-1 and IRS-2, respectively, in normal pregnant ovaries and human
cultured follicles. Immunohistochemical staining showed that positive IRS-2
expression in antral follicles was restricted to theca internal cells in
ovulatory ovaries but was distributed widely in all compartments of follicles
in different stages in polycystic ovaries. Compared with follicles at a
similar stage of development in ovulatory ovaries, follicles in polycystic
ovaries showed decreased staining for IRS-1 in granulosa cells but increased
staining for IRS-2 in theca internal cells. This study highlights a shift of the follicular insulin signal
protein from IRS-1 to IRS-2 in insulin-resistant states and suggests an
association between this change and ovarian abnormality in PCOS and
gestational diabetes mellitus.
Follicle stages
Antral
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
3 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Severe dietary restriction, catabolic states and even short-term caloric
deprivation impair
fertility in mammals. Likewise, obesity is associated with infertile
conditions such as
polycystic ovary syndrome. The reproductive status of lower organisms such as
Caenorhabditis elegans is also modulated by availability of nutrients.
Thus, fertility requires
the integration of reproductive and metabolic signals. BURKS, et al reported that IRS-2 pathways integrate female reproduction and energy
homeostasis. They show that
deletion of insulin
receptor substrate-2 (IRS-2), a component of the insulin/insulin-like
growth factor-1
signalling cascade, causes female infertility. Mice lacking IRS-2 have
small, anovulatory
ovaries with reduced numbers of follicles. Quantitation of primary oocytes from embryos at day 18.5 revealed reduced numbers in mutant mice. Plasma concentrations of
luteinizing hormone,
prolactin and sex steroids are low in these animals. Pituitaries are
decreased in size and
contain reduced numbers of gonadotrophs. Females lacking IRS-2 have
increased food intake
and obesity, despite elevated levels of leptin.
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment:Withers DJ reported that analysis of IRS-2 knockout mice shows that female mice are infertile owing
to defects in the hypothalamus, pituitary and gonad. IRS-2(-/-) mice have small, anovulatory ovaries with reduced numbers of follicles. Levels of the
pituitary hormones luteinizing hormone and prolactin and gonadal steroids are
low in these animals. Pituitaries of IRS-2(-/-) animals are decreased in size
and contain reduced numbers of gonadotrophs. Additionally, IRS-2(-/-) females
display increased food intake and develop obesity, despite elevated leptin
levels, suggesting abnormalities in hypothalamic function.
Species: human
Mutation name: None
type: naturally occurring fertility: fertile Comment: Study of association of IRS-1 and IRS-2 genes polymorphisms with clinical and metabolic features in women with polycystic ovary syndrome. Is there an impact? Christopoulos P et al. Objective. Insulin receptor substrate (IRS) proteins are critical to signal transduction in insulin target tissues. The present study was undertaken to determine whether IRS-1 Gly972Arg and IRS-2 Gly1057Asp influence hormonal and metabolic characteristics in Greek patients with polycystic ovary syndrome (PCOS) and controls. Material and methods. One hundred and eighty-three women with PCOS and 88 healthy volunteers were enrolled. Venous blood samples were obtained for genetic study and hormonal profile, glucose, and insulin assays, on days 3 to 7 from cycling patients. DNA was extracted by whole blood samples for genotyping and detection of IRS-1 Gly972Arg and IRS-2 Gly1057Asp polymorphisms. Results. Fifty-six women with PCOS (30.60%), whereas 12 women in the control group (13.64%) carried the IRS-1 polymorphism (p = 0.0026). No statistically significant differences in genotypes or allele frequencies for IRS-2 polymorphism were observed between controls and PCOS women. No significant differences in any clinical or hormonal measures between subjects on the basis of genotype were observed, except the increased levels of fasting glucose that exhibit the carriers of the Asp allele of the IRS-2 polymorphism. Conclusions. Only the IRS-1 polymorphism is associated with increased susceptibility to PCOS in a Greek population. These loci should not be considered as major contributors to the hormonal and metabolic phenotype of PCOS.