Increased Insulin Sensitivity and Hypoinsulinemia in APS Knockout Mice

Abstract

A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS ؊/؊ ) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS ؊/؊ mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS ؊/؊ mice. APS ؊/؊ mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS ؊/؊ mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS ؊/؊ mice was increased over that of APS ؉/؉ mice. APS ؊/؊ mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes. Diabetes 52: [2657][2658][2659][2660][2661][2662][2663][2664][2665] 2003 I nsulin signaling begins with the binding of insulin to its receptor present on the cell surface, and activation of the insulin receptor tyrosine kinase results in tyrosine phosphorylation of a number of intracellular substrates. These molecules, including the insulin receptor substrate (IRS) family (1), src homology and collagen (2), Gab1 (3), and Grb10 (4), act as adaptor molecules that link between the insulin receptor and downstream signaling effectors. Adaptor protein containing a pleckstrin homology and SH2 domain (APS) is also one of the substrates that tyrosine phosphorylated by insulin receptor kinase (5,6).APS was first described to interact with an oncogenic mutant of the tyrosine kinase receptor c-Kit (7), and APS was isolated by the two-hybrid system using the cytoplasmic domain of the human insulin receptor as bait (5,6). APS (66.5 kDa) forms an adaptor protein family together with Lnk (8,9) and SH2-B (SH2-B␣, SH2-B␤, SH2-B␥, and SH2-B␦) (10 -13), whose members share a homologous NH 2 -terminal region with proline-rich stretches, pleckstrin homology and SH2 domains, and a conserved COOHterminal tyrosine phosphorylation site. It has been demonstrated that some members of this adaptor protein family act as modulators of signaling through various tyrosine kinase receptors. Lnk plays a role in regulating production of B-cell precursors and hematopoietic progenitor cells (8,14). SH2-B is an important signaling molecule in the insulin-like growth factor I (IGF-1) mediated reproductive pathway (13).APS is highly expressed in insulin-r...

The molecular basis of insulin-stimulated glucose uptake: signalling, trafficking and potential drug targets

“…However, the siRNAmediated ablation of Cbl, CAP and CrkII do not have any significant effect on insulin-stimulated glucose uptake or GLUT4 translocation , Zhou et al 2004. Furthermore, while the generation of Cbl knockout mice does not result in a significant difference in insulin sensitivity (Molero et al 2004), APS knockout mice show enhanced insulin sensitivity and hypoinsulinaemia (Minami et al 2003). Finally, studies performed in muscle cells indicate that TC10 signalling may not be required for cortical actin rearrangements as has been shown in adipocytes ( JeBailey et al 2004).…”

Enhanced Fasting Glucose Turnover in Mice with Disrupted Action of TUG Protein in Skeletal Muscle

“…The TC10␣ isoform is highly expressed in muscle and fat and was activated by insulin in most studies (50,53,54). Mediators of insulin signaling to TC10␣ remain uncertain; in particular, disruption of the proposed signaling proteins APS and c-Cbl did not impair, but actually enhanced, insulin action (49,(55)(56)(57)(58)(59). Other proteins may mediate upstream signaling (60).…”

Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells

“…12 Mice deficient for members of this family have demonstrated the positive (SH2-B) and negative (Lnk and APS) role of these adaptors in growth factor, cytokine, and antigen-receptor signaling. [13][14][15][16][17][18] In particular, Lnk nullizygous mice show mainly a profound perturbation in hematopoiesis. These animals exhibit splenomegaly together with fibrosis, expansion of hematopoietic stem cells (HSCs), and myeloid and B lymphoid progenitors.…”