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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046504-08
Application #
7197299
Study Section
Special Emphasis Panel (ZRG1-MOSS-H (02))
Program Officer
Boyce, Amanda T
Project Start
1999-12-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
8
Fiscal Year
2007
Total Cost
$341,061
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Shi, Hao; Verma, Mayank; Zhang, Lei et al. (2013) Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5. J Clin Invest 123:2064-77
Shi, Hao; Boadu, Emmanuel; Mercan, Fatih et al. (2010) MAP kinase phosphatase-1 deficiency impairs skeletal muscle regeneration and exacerbates muscular dystrophy. FASEB J 24:2985-97
Flach, Rachel J Roth; Bennett, Anton M (2010) MAP kinase phosphatase-1--a new player at the nexus between sarcopenia and metabolic disease. Aging (Albany NY) 2:170-6
Jeanneteau, Freddy; Deinhardt, Katrin; Miyoshi, Goichi et al. (2010) The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching. Nat Neurosci 13:1373-9
Yu, Luyang; Min, Wang; He, Yun et al. (2009) JAK2 and SHP2 reciprocally regulate tyrosine phosphorylation and stability of proapoptotic protein ASK1. J Biol Chem 284:13481-8
Carlson, Jodi; Cui, Weiguo; Zhang, Qing et al. (2009) Role of MKP-1 in osteoclasts and bone homeostasis. Am J Pathol 175:1564-73
Eminaga, Seda; Bennett, Anton M (2008) Noonan syndrome-associated SHP-2/Ptpn11 mutants enhance SIRPalpha and PZR tyrosyl phosphorylation and promote adhesion-mediated ERK activation. J Biol Chem 283:15328-38
Zito, Christina I; Qin, Hui; Blenis, John et al. (2007) SHP-2 regulates cell growth by controlling the mTOR/S6 kinase 1 pathway. J Biol Chem 282:6946-53
Uhlen, Per; Burch, Peter M; Zito, Christina Ivins et al. (2006) Gain-of-function/Noonan syndrome SHP-2/Ptpn11 mutants enhance calcium oscillations and impair NFAT signaling. Proc Natl Acad Sci U S A 103:2160-5
Fornaro, Mara; Burch, Peter M; Yang, Wentian et al. (2006) SHP-2 activates signaling of the nuclear factor of activated T cells to promote skeletal muscle growth. J Cell Biol 175:87-97

Showing the most recent 10 out of 13 publications