The broad goal of this research is to define the function of protein tyrosine phosphatases (PTPs) in skeletal muscle biology. The equilibrium between the opposing actions of protein tyrosine kinases (PTKs) and PTPs in the regulation of cellular protein tyrosyl phosphorylation is essential for development, growth and differentiation. Although it is well established that PTKs play a critical role in regulating muscle development, growth and regeneration, little is known about how PTPs participate in these processes. The specific goal of this research is to define the role of SHP-2, a Src homology 2 domain-containing PTP, in developmental and post-developmental skeletal muscle function. Aberrant regulation of SHP-2 has been linked to an inherited disease in humans called Noonan syndrome (NS) which represents approximately 1:2,000 live births. NS manifests as an array of abnormalities, most notably those of the cardiac and musculoskeletal systems. However, the signaling pathways regulated by SHP-2 during skeletal muscle development and in mature differentiated muscle are largely unknown. Therefore, the aims of this research are; (i) define the role of SHP-2 during myogenic development, (ii) determine SHP-2's role in regulating muscle growth, and (iii) identify and characterize the mechanism of action of SHP-2 substrates in skeletal muscle function. These objectives will be accomplished using Cre-LoxP-mediated conditional deletion of SHP-2, either eady in the myogenic lineage to study its role in development, or later in the myogenic lineage, to establish the effects of muscle-specific ablation of SHP-2 post-developmentally. Substrates of SHP-2 in skeletal muscle will be identified using SHP-2 """"""""substrate trapping"""""""" strategies combined with MS/MS mass spectrometry. The information derived from these studies will provide novel insights into the signaling networks that control muscle function. New therapeutic avenues for diseases that compromise muscle function such as the muscular dystrophies, cancer and Noonan syndrome may emerge from these studies.
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