“The Role of the SH2 Domain-Containing Protein Tyrosine Phosphatase, SHP-2, in Nutrient Responsive mTOR Signaling”
Fatih Mercan, Ph.D.
Department of Pharmacology, Yale University School of Medicine
Amino acids are required for the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway that plays a critical role in regulating 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). The mechanism through which leucine activates S6K1 has yet to be completely elucidated. 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 lacking SHP-2. Activation of S6K1 by leucine requires the release of calcium (Ca2+) in an inositol-1,4,5-trisphosphate-dependent manner from intracellular stores. Ectopic mobilization of Ca2+ rescues the S6K1 activation defect in SHP-2-deficient myoblasts. We show that myoblasts lacking SHP‑2 are defective in their ability to mobilize Ca2+ which was attributed to impaired generation of inositol-1,4,5-trisphosphate. We found that nutrient-induced S6K1 activation required engagement of both tyrosine kinase and G-protein coupled receptor pathways. However, activation of the G-protein coupled receptor pathway linked to phospholipase C b4, rather than activation of phospholipase Cg by tyrosine kinases, was responsible for nutrient-induced 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 downstream of G protein-coupled receptors in nutrient-mediated Ca2+ activation that is required for mTORC1/S6K1 signaling.
Dr. Fatih Mercan received his Bachelor of Science degree from Bilkent University Molecular Biology and Genetics Department in 2004. Then he went on to get his Ph.D. degree from Yale University at the laboratory of Dr. Anton M. Bennett. During his graduate studies he worked on the role of protein tyrosine phosphatases (PTPs) in various aspects of cellular signaling. His work at the Bennett lab spans from PTPs in musculoskeletal biology to their role in cellular metabolism. He won the American Foundation for Aging Research Foundation Fellowship in 2006. Today Dr. Mercan will be talking about his dissertation work entitled “The Role of the SH2 Domain-Containing Protein Tyrosine Phosphatase, SHP-2, in Nutrient Responsive mTOR Signaling”.