Grb10 and Grb14
: enigmatic regulators of insulin action--and more?
) gene that encodes a growth factor receptor-binding protein.
The growth factor receptor-bound protein 10 (Grb10) is a member of the Grb7 family adaptor molecules that includes Grb10, Grb14 and Grb7 proteins.
Dual ablation of Grb10 and Grb14 in mice reveals their combined role in regulation of insulin signaling and glucose homeostasis.
SNPs found to be associated with T2D in Asian popula tions, rs1048886 (C6orf57) , rs4402960 (IGF2BP2) , rs5015480 (HHEX, IDE), rs1359790 (SPRY2) , rs1552224 (CENTD2), rs3923113 (GRB14
), rs5215 (KCNJ11), rs7903146 (TCF7L2) , rs10886471 (GRK5), and rs7403531 (RASGRP1) , were not replicated in our study.
SH2 domain containing proteins such as growth factor receptor-bound protein 2 (GRB2), growth factor receptor-bound protein 7 (GRB7), growth factor receptor-bound protein 14 (GRB14
), protein tyrosine phosphatase nonreceptor type 11 (SHP-2), and phosphoinositide-3-kinase (PI3K) is recruited and transphosphorylated by TIE2 .
Feedback at these levels may involve uncoupling of the receptor and IRS, for example, by Grb10 and Grb14
, inhibition of the receptor tyrosine kinase activity by suppressors of cytokine signaling (SOCS proteins), or obstructing activation of Akt the binding of Trb3 (Tribbles homolog 3) pseudokinases .
Using the same method, seven highly ranked genes (BAP1, GRB14, HSP90AB1, ITGA5, NCKAP5L, SP1, and TOMM5) within [+ or -] 1 Mb of obesity SNPs were identified (Table 2).
Results of GO and pathway analyses revealed that PRKCB is mainly associated with T2DM, and PRKCB and GRB14 are involved in insulin signaling within the gene pathway network (Figure 2).
For example, rGrb14, the rat homologue of the human growth factor receptor, bound human Grb14 adaptor protein, a direct inhibitor of the activated insulin receptor (Bereziat et al.
Inhibition of insulin receptor catalytic activity by the molecular adapter Grb14. J Biol Chem 277:4845-4852.
Using a relatively modest sample size (5,561 cases and 14,458 controls in the discovery step) five additional novel T2D loci were discovered : HNF4A, involved in monogenic forms of diabetes and associated with [beta]-cell development ; GRB14
which is associated with obesity and insulin resistance ; and another three loci with less clear functions; AP3S2, ST6GAL1 and VPS26A .