The mitogen-activated protein kinases (MAPKs) are inactivated by direct dephosphorylation by a family of enzymes known as MAPK phosphatases (MKPs). The MKPs exert unique physiological outcomes by acting as signaling nodes that integrate multiple MAPK activities. The MAPKs are essential positive regulators of regenerative myogenesis. A complete understanding of how the MAPKs are inactivated during regenerative myogenesis has yet to be achieved. Muscle stem cells are required for regenerative myogenesis and their dysfunction causes degenerative skeletal muscle disease. We have identified MKP5 as an essential MKP that opposes MAPK signaling in skeletal muscle and maintains muscle stem cell quiescence. MKP5 deletion in a mouse model of dystrophic muscle disease ameliorates muscular dystrophy. Hence, MKP5 represents a potential therapeutic target for the treatment of dystrophic muscle disease. The degeneration of skeletal muscle function in congenital dystrophic muscle disease leads to death in young male adults and there is neither a cure nor treatment for this disease. We propose a multi-disciplinary plan encompassing the use of mouse genetics, cell biology, phosphoproteomics, structural biology and chemical biology strategies towards defining MKP5 function in muscle stem cells, skeletal muscle function and a potential therapeutic target for the treatment of degenerative skeletal muscle disease.
Aim 1 will define the genetic link between MKP5 and JNK dephosphorylation in regenerative myogenesis. How MKP5 participates in maintaining myofiber homeostasis through control of mitochondrial function will be defined.
Aim 2 will employ phosphoproteomic strategies to identify and characterize MKP5-regulated MAPK substrates involved in muscle stem cell function and myofiber integrity.
Aim 3, will utilize chemical biology approaches to identify MKP5 small molecule inhibitors. Identified MKP5 inhibitors will be used to provide proof-of- principle for the validity of MKP5 inhibition as a therapeutic target for dystrophic muscle disease. If successful, this work will lay the foundation for new avenues of investigation towards MKP5 as a target for the treatment of degenerative skeletal muscle disease.

Public Health Relevance

This project will define the physiological and pathophysiological involvement of MAP kinase phosphatases in skeletal muscle biology. Molecules that antagonize the MAPKs, known as MAP kinase phosphatases, will be the primary focus of this project. Uncovering how the MAPK phosphatases integrate signals that control skeletal muscle homeostasis will provide new insight into the pathogenesis of skeletal muscle diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR066003-04
Application #
9395792
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Cheever, Thomas
Project Start
2015-02-02
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
Levy, Aaron D; Xiao, Xiao; Shaw, Juliana E et al. (2018) Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function. Cell Rep 24:1523-1535
Lee, Hojin; Min, Kisuk; Yi, Jae-Sung et al. (2017) A Phosphoproteomic Screen Identifies a Guanine Nucleotide Exchange Factor for Rab3A Protein as a Mitogen-activated Protein (MAP) Kinase Phosphatase-5-regulated MAP Kinase Target in Interleukin 6 (IL-6) Secretion and Myogenesis. J Biol Chem 292:3581-3590
Tzouvelekis, Argyrios; Yu, Guoying; Lino Cardenas, Christian L et al. (2017) SH2 Domain-Containing Phosphatase-2 Is a Novel Antifibrotic Regulator in Pulmonary Fibrosis. Am J Respir Crit Care Med 195:500-514
Min, Kisuk; Lawan, Ahmed; Bennett, Anton M (2017) Loss of MKP-5 promotes myofiber survival by activating STAT3/Bcl-2 signaling during regenerative myogenesis. Skelet Muscle 7:21
Yi, Jae-Sung; Huang, Yan; Kwaczala, Andrea T et al. (2016) Low-dose dasatinib rescues cardiac function in Noonan syndrome. JCI Insight 1:e90220
Shi, Hao; Gatzke, Florian; Molle, Julia M et al. (2015) Mice lacking MKP-1 and MKP-5 Reveal Hierarchical Regulation of Regenerative Myogenesis. J Stem Cell Regen Biol 1:1-7
Lawan, Ahmed; Zhang, Lei; Gatzke, Florian et al. (2015) Hepatic mitogen-activated protein kinase phosphatase 1 selectively regulates glucose metabolism and energy homeostasis. Mol Cell Biol 35:26-40
Lee, Hojin; Yi, Jae-Sung; Lawan, Ahmed et al. (2015) Mining the function of protein tyrosine phosphatases in health and disease. Semin Cell Dev Biol 37:66-72