Activation of the bone morphogenetic protein receptor by H11kinase/Hsp22 promotes cardiac cell growth and survival.
H11 kinase/Hsp22 (H11K) is a chaperone promoting cardiac cell growth and survival through the activation of Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K). In this study, we tested whether H11K-induced activation of the PI3K/Akt pathway is mediated by the bone morphogenetic protein (BMP) signaling, both in a transgenic mouse model with cardiac-specific overexpression of H11K and in isolated cardiac myocytes. Microarrays in hearts from transgenic compared to wild-type mice showed an upregulation of the BMP receptors Alk3 and BMPR-II, and of their ligand BMP4 (P<0.01 versus wild type). Activation of the BMP pathway in transgenic mice was confirmed by increased phosphorylation of the "canonical" BMP effectors Smad 1/5/8 (P<0.01 versus wild type). In isolated myocytes, adenovirus-mediated overexpression of H11K was accompanied by a significant (P<0.01) increase in PI3K activity, phospho-Akt, Smad 1/5/8 phosphorylation and [(3)H]phenylalanine incorporation, and by a 70% reduction in H(2)O(2)-mediated apoptosis. All these effects were abolished by the BMP antagonist noggin. In presence of BMP4, Smad 1/5/8 phosphorylation was enhanced by 5-fold on H11K overexpression but decreased by 3-fold on H11K knockdown (P<0.01 versus control), showing that H11K potentiates the BMP signaling. In pull-down experiments, H11K increased both the association of Alk3 and BMPR-II together, and their interaction with the transforming growth factor-beta-activated kinase (TAK)1, a "noncanonical" mediator of the BMP receptor signaling. TAK1 inhibition prevented H11K-mediated activation of Akt. Therefore, potentiation of the BMP receptor by H11K promotes an activation of the PI3K/Akt pathway mediated by TAK1, which dictates the physiological effects of H11K on cardiac cell growth and survival.
Sui
Xiangzhen
X
Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103, USA.
Li
Dan
D
Qiu
Hongyu
H
Gaussin
Vinciane
V
Depre
Christophe
C
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D014161:Transduction, Genetic; D000099176:Noggin Protein; D000099151:MAP Kinase Kinase Kinase 7
D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D020930:MAP Kinase Kinase Kinases; D018832:Molecular Chaperones; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051896:Smad Proteins, Receptor-Regulated; D000099176:Noggin Protein; D000099151:MAP Kinase Kinase Kinase 7; C525810:Bmp4 protein, mouse; C413214:HSPB8 protein, human; C498212:Bmpr1a protein, mouse; C498219:Bmpr2 protein, mouse