Abstract
Protein tyrosine phosphatase-like A (PTPLa) has been implicated in skeletal myogenesis and cardiogenesis. Mutations in PTPLa correlated with arrhythmogenic right ventricular dysplasia in humans and congenital centronuclear myopathy with severe hypotonia in dogs. The molecular mechanisms of PTPLa in myogenesis are unknown. In this report, we demonstrate that PTPLa is required for myoblast growth and differentiation. The cells lacking PTPLa remained immature and failed to differentiate into mature myotubes. The repressed MyoG expression was responsible for the impaired myoblast differentiation. Meanwhile, impeded cell growth, with an obvious S-phase arrest and compromised G2/M transition, was observed in PTPLa-deficient myoblasts. Further study demonstrated that the upregulation of cyclin D1 and cyclin E2 complexes, along with a compromised G2/M transition due to the decreased CDK1 (cyclin-dependent kinase 1) activity and upregulated p21, contributed to the mutant cell S-phase arrest and eventually led to the retarded cell growth. Finally, the transcriptional regulation of the PTPLa gene was explored. We identified PTPLa as a new target gene of the serum response factor (SRF). Skeletal- and cardiac-muscle-specific SRF knockouts resulted in significant decreases in PTPLa expression, suggesting a conserved transcriptional regulation of the PTPLa gene in mice.
ACKNOWLEDGMENTS
We thank Dafe Uwanogho for the critical discussion on the project. We are grateful to Vladimir N. Potaman and Alexis Boggs for editorial assistance to the manuscript.
This work was supported by the NIH-NHLBI (grants R01HL102314, R21HL094844, and K02HL098956) and by AHA grant-in-aid 0855030F (to J.C.), the NSFC (grants 30860103 and 81060175 to Q.L.), and the National Grant of Basic Research Program of China (grants 2010CB912203 and 2011CB915504 to D.H.).