title: Glyceraldehyde-3-phosphate dehydrogenase interacts with proapoptotic kinase mst1 to promote cardiomyocyte apoptosis.
abstract: Mammalian sterile 20-like kinase 1 (Mst1) 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 the heart disease since its activation causes cardiomyocyte apoptosis and dilated cardiomyopathy. However, the mechanism underlying Mst1 activation in the heart remains unknown. In a yeast two-hybrid screen of a human heart cDNA library with Mst1 as bait, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified as an Mst1-interacting protein. The interaction of GAPDH with Mst1 was confirmed by co-immunoprecipitation in both co-transfected HEK293 cells and mouse heart homogenates, in which GAPDH interacted with the kinase domain of Mst1, whereas the C-terminal catalytic domain of GAPDH mediated its interaction with Mst1. Moreover, interaction of Mst1 with GAPDH caused a robust phosphorylation of GAPDH and markedly increased the Mst1 activity in cells. Chelerythrine, a potent inducer of apoptosis, substantially increased the nuclear translocation and interaction of GAPDH and Mst1 in cardiomyocytes. Overexpression of GAPDH significantly augmented the Mst1 mediated apoptosis, whereas knockdown of GAPDH markedly attenuated the Mst1 activation and cardiomyocyte apoptosis in response to either chelerythrine or hypoxia/reoxygenation. These findings reveal a novel function of GAPDH in Mst1 activation and cardiomyocyte apoptosis and suggest that disruption of GAPDH interaction with Mst1 may prevent apoptosis related heart diseases such as heart failure and ischemic heart disease.
authors.affiliation: Institute of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Bei
authors.initials: B
authors.lastname: You
authors.forename: Shengdong
authors.initials: S
authors.lastname: Huang
authors.forename: Qing
authors.initials: Q
authors.lastname: Qin
authors.forename: Bing
authors.initials: B
authors.lastname: Yi
authors.forename: Yang
authors.initials: Y
authors.lastname: Yuan
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Xu
authors.forename: Jianxin
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D055785:Gene Knockdown Techniques; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology*; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020798:Two-Hybrid System Techniques; D000099317:Hippo Kinases
chemical_list: D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D017228:Hepatocyte Growth Factor; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C095566:STK4 protein, human