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Mol Cell Biol. 2013 Jan;33(2):293-306. doi: 10.1128/MCB.01285-12. Epub 2012 Nov 5.

Novel role for SHP-2 in nutrient-responsive control of S6 kinase 1 signaling.

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Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.


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 (Ca(2+)), which we show is mediated by SHP-2 in an inositol-1,4,5-trisphosphate-dependent manner. Ectopic Ca(2+) mobilization rescued the S6K1 activation defect in SHP-2-deficient myoblasts. SHP-2 was identified to act upstream of phospholipase C β4, linking it to the generation of nutrient-induced Ca(2+) 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.

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