NCBI Summary:
This gene encodes a member of the SH2B adaptor family of proteins, which are involved in a range of signaling activities by growth factor and cytokine receptors. The encoded protein is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. Mutations in this gene have been associated with susceptibility to celiac disease type 13 and susceptibility to insulin-dependent diabetes mellitus. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]
General function
Intracellular signaling cascade
Comment
Cellular localization
Cytoplasmic
Comment
Ovarian function
Follicle atresia
Comment
LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway. Tan M et al. (2021) Polycystic ovary syndrome (PCOS), which is often accompanied by insulin resistance, is closely related to increased apoptosis of ovarian granulosa cells. LNK is an important regulator of the insulin signaling pathway. When insulin binds to the receptor, the PI3K/AKT/FOXO signaling pathway is activated, and FOXO translocates from the nucleus to the cytoplasm, thereby inhibiting the expression of pro-apoptotic genes. Granulosa cells were collected from PCOS patients to investigate the relationship between LNK, cell apoptosis and insulin resistance. KGN cells underwent LNK overexpression/silence and insulin stimulation. The AKT/FOXO3 pathway was studied by western blot and immunofluorescence. LNK knockout mice were used to investigate the effect of LNK on the pathogenesis of PCOS. The level of LNK was higher in PCOS group than control group. LNK was positively correlated with granulosa cell apoptosis and insulin resistance, and negatively correlated with oocyte maturation rate. LNK overexpression in KGN cells inhibited insulin-induced AKT/FOXO3 signaling pathway, causing nucleus translocation of FOXO3 and promoting granulosa cell apoptosis. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice. LNK was closely related to insulin resistance and apoptosis of granulosa cells via the AKT/FOXO3 pathway. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice, suggesting LNK might become a potential biological target for the clinical treatment of PCOS.//////////////////
Expression regulated by
Comment
Ovarian localization
Granulosa
Comment
Over-expression of Lnk in the ovaries was involved in insulin resistance in the women with polycystic ovary syndrome. Hao M et al. (2016) Polycystic ovary syndrome (PCOS) progression involves abnormal insulin signaling. Lnk may be an important regulator of the insulin signaling pathway. We investigated whether Lnk was involved in insulin resistance. Thirty-seven women due to receive laparoscopic surgery from June 2011 to February 2012 were included from the gynecologic department of the Sun Yat-Sen Memorial hospital, Sun Yat-Sen University, Guangzhou, China. Samples of polycystic and normal ovary tissues were examined by immunohistochemistry. Ovarian cell lines underwent insulin stimulation and Lnk over-expression. Expressed Lnk underwent co-immunoprecipitation tests with GFP-labeled insulin receptor and His-tagged insulin receptor substrate 1 (IRS1), and their co-localization in HEK293T cells was examined. Ovarian tissues from PCOS patients with insulin resistance exhibited higher expression of Lnk than ovaries from normal control subjects and PCOS patients without insulin resistance; mainly in follicular granulose cells, the follicular fluid and plasma of oocytes in secondary follicles, and atretic follicles. Lnk was co-immunoprecipitated with insulin receptor and IRS1. Lnk and insulin receptor/IRS1 locations overlapped around the nucleus. IR, Akt, and ERK1/2 activities were inhibited by Lnk over-expression and inhibited further after insulin stimulation while IRS1 serine activity was increased. Insulin receptor (Tyr1150/1151), Akt (Thr308) and ERK1/2(Thr202/Tyr204) phosphorylation was decreased while IRS1 (Ser307) phosphorylation was increased with Lnk over-expression. In conclusion, Lnk inhibits the PI3K-AKT and MAPK-ERK signaling response to insulin. Higher expression of Lnk in polycystic ovary syndrome suggests that Lnk probably plays a role in the development of insulin resistance.//////////////////