title: Protein-L-isoaspartate (D-aspartate) O-methyltransferase protects cardiomyocytes against hypoxia induced apoptosis through inhibiting proapoptotic kinase Mst1.
abstract: BACKGROUND
  Mammalian sterile 20-like kinase 1 (Mst1) is a mammalian homolog of Hippo kinase from Drosophila and it is a critical component of the Hippo signaling pathway, which regulates a variety of biological processes ranging from cell contact inhibition, organ size control, apoptosis and tumor suppression in mammals. Mst1 plays essential roles in heart disease since its activation causes cardiomyocyte apoptosis and dilated cardiomyopathy. However, the mechanism underlying Mst1 activation in the heart is not known.
  
  
  RESULTS
  To identify novel cardiac proteins that may regulate Mst1 activity in the heart under pathophysiological conditions, a yeast two-hybrid screening of a human heart cDNA library with a dominant-negative Mst1 (K59R) mutant used as bait was performed. As a result, protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) was identified as an Mst1-interacting protein. The interaction of PCMT1 with Mst1 was confirmed by co-immunoprecipitation in both co-transfected HEK293 cells and native cardiomyocytes, in which PCMT1 interacted with the kinase domain of Mst1, but not with its C-terminal regulatory domain. Overexpression of PCMT1 did not affect the Mst1 expression, but significantly attenuated the Mst1 activation and its apoptotic effects in response to the hypoxia/reoxygenation induced injury in cardiomyocytes. Indeed, upregulation of PCMT1 by CGP3466B, a compound related to the anti-Parkinson's drug R-(-)-deprenyl with potent antiapoptotic effects, inhibited the hypoxia/reoxygenation induced Mst1 activation and cardiomyocyte apoptosis.
  
  
  CONCLUSIONS
  These findings implicate PCMT1 as a novel inhibitor of Mst1 activation in cardiomyocytes and suggest that targeting PCMT1 may prevent myocardial apoptosis through inhibition of Mst1.
authors: Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; Reproductive Medicine Center, The Affiliated Drum Tower Hospital of Nanjing University, Nanjing, China.
authors: Guijun
authors: G
authors: Yan
authors: Qing
authors: Q
authors: Qin
authors: Bing
authors: B
authors: Yi
authors: Kurt
authors: K
authors: Chuprun
authors: Haixiang
authors: H
authors: Sun
authors: Shengdong
authors: S
authors: Huang
authors: Jianxin
authors: J
authors: Sun
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D002316:Cardiotonic Agents / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism*; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099317:Hippo Kinases
chemical_list: D002316:Cardiotonic Agents; D047908:Intracellular Signaling Peptides and Proteins; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase; D017346:Protein Serine-Threonine Kinases; C435725:PCMT1 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases
keywords: Apoptosis; Cardiac myocytes; Hypoxia/reoxygenation; Mst1 kinase; PCMT1
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