The interactions of CAP and LYN with the insulin signaling transducer CBL play an important role in polycystic ovary syndrome
Abstract
Background Polycystic ovary syndrome (PCOS) is a hormonal disorder characterized by hyperandrogenism, ovulatory dysfunction, and insulin resistance. Evidence suggests that aberrations in insulin signaling-associated pathways may underlie PCOS pathogenesis. Our aim was to investigate the molecular mechanisms underlying PCOS and associated insulin resistance using in silico analyses, in vitro cell models, and in vivo murine models. Methods R-based bioinformatics analysis was performed on granulosa cell microarray data from three human cohorts: healthy control, PCOS patients without insulin resistance, and PCOS patients with insulin resistance. Transgenic human granulosa cell models were utilized for in vitro studies. Transgenic murine models of dehydroepiandrosterone (DHEA)-induced PCOS were utilized for in vivo studies. Results Sorbin and SH3 Domain Containing 1 ( SORBS1 ) , the parent gene of the insulin receptor-associated Casitas B-lineage lymphoma protein (CBL)-associated protein (CAP), is a key downregulated gene in PCOS patients with insulin resistance. CAP binding to CBL reduced CBL Y731 phosphorylation, CBL-phosphoinositide 3-kinase (PI3K) p85α interactivity, protein kinase B (Akt) S473 phosphorylation, and NFκB-induced inflammatory marker expression but enhanced CRKII-mediated membrane GLUT4 translocation in granulosa cells. In contrast, the tyrosine kinase Lck/Yes-Related Novel Protein (LYN) is upregulated in PCOS patients with insulin resistance. LYN binding to CBL…
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