Novel Role for SHP-2 in Nutrient-Responsive Control of S6 Kinase 1 Signaling

作者：Mercan Fatih; Lee Hojin; Kolli Sivanagarani; Bennett Anton M^*

来源：Molecular and Cellular Biology, 2013, 33(2): 293-306.

DOI：10.1128/MCB.01285-12

Amino acids are required for the activation of the mammalian target of rapamycin complex 1 (mTORC1), which plays a critical role in cell growth, proliferation, and metabolism. The branched-chain amino acid leucine is an essential nutrient that stimulates mTORC1 to promote protein synthesis by activating p70 S6 kinase 1 (S6K1). Here we show that the protein tyrosine phosphatase SHP-2 is required for leucine-induced activation of S6K1 in skeletal myoblasts. In response to leucine, S6K1 activation is inhibited in myoblasts either lacking SHP-2 expression or overexpressing a catalytically inactive mutant of SHP-2. Activation of S6K1 by leucine requires the mobilization of intracellular calcium (Ca2+), which we show is mediated by SHP-2 in an inositol-1,4,5-trisphosphate-dependent manner. Ectopic Ca2+ mobilization rescued the S6K1 activation defect in SHP-2-deficient myoblasts. SHP-2 was identified to act upstream of phospholipase C beta 4, linking it to the generation of nutrient-induced Ca2+ release and S6K1 phosphorylation. Consistent with these results, SHP-2-deficient myoblasts exhibited impaired leucine sensing, leading to defective autophagy and reduced myoblast size. These data define a new role for SHP-2 as a nutrient-sensing regulator in skeletal myoblasts that is required for the activation of S6K1.

• 出版日期2013-1