title: Overexpression of Lnk in the Ovaries Is Involved in Insulin Resistance in Women With Polycystic Ovary Syndrome.
abstract: Polycystic ovary syndrome (PCOS) progression involves abnormal insulin signaling. SH2 domain-containing adaptor protein (Lnk) may be an important regulator of the insulin signaling pathway. We investigated whether Lnk was involved in insulin resistance (IR). 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. Samples of polycystic and normal ovary tissues were examined by immunohistochemistry. Ovarian cell lines underwent insulin stimulation and Lnk overexpression. Expressed Lnk underwent coimmunoprecipitation tests with green fluorescent protein-labeled insulin receptor and His-tagged insulin receptor substrate 1 (IRS1), and their colocalization in HEK293T cells was examined. Ovarian tissues from PCOS patients with IR exhibited higher expression of Lnk than ovaries from normal control subjects and PCOS patients without IR; mainly in follicular granulosa cells, the follicular fluid and plasma of oocytes in secondary follicles, and atretic follicles. Lnk was coimmunoprecipitated with insulin receptor and IRS1. Lnk and insulin receptor/IRS1 locations overlapped around the nucleus. IR, protein kinase B (Akt), and ERK1/2 activities were inhibited by Lnk overexpression and inhibited further after insulin stimulation, whereas IRS1 serine activity was increased. Insulin receptor (Tyr1150/1151), Akt (Thr308), and ERK1/2 (Thr202/Tyr204) phosphorylation was decreased, whereas IRS1 (Ser307) phosphorylation was increased with Lnk overexpression. In conclusion, Lnk inhibits the phosphatidylinositol 3 kinase-AKT and MAPK-ERK signaling response to insulin. Higher expression of Lnk in PCOS suggests that Lnk probably plays a role in the development of IR.
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Meihua
authors.initials: M
authors.lastname: Hao
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Feng
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Zehong
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Guanlei
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Dongzi
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Meiqing
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Obstetrics and Gynecology (M.H., H.H., D.Y., M.X., X.Z.), Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Pharmacology (F.Y., C.J., G.W.), Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510120 China; Department of Obstetrics and Gynecology (Z.Z.), Reproductive Medical Center, Peking University Third Hospital, Haidian District, Beijing, China; Division of Hematology/Oncology (Q.C.), Cedar-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California; and Cedar-Sinai Medical Center (L.X.), University of California, Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Xiaomiao
authors.initials: X
authors.lastname: Zhao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D010053:Ovary / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; C526292:IRS1 protein, human; C490778:SH2B3 protein, human