BAG3 controls angiogenesis through regulation of ERK phosphorylation.
BAG3 is a co-chaperone of the heat shock protein (Hsp) 70, is expressed in many cell types upon cell stress, however, its expression is constitutive in many tumours. We and others have previously shown that in neoplastic cells BAG3 exerts an anti-apoptotic function thus favoring tumour progression. As a consequence we have proposed BAG3 as a target of antineoplastic therapies. Here we identify a novel role for BAG3 in regulation of neo-angiogenesis and show that its downregulation results in reduced angiogenesis therefore expanding the role of BAG3 as a therapeutical target. In brief we show that BAG3 is expressed in endothelial cells and is essential for the interaction between ERK and its phosphatase DUSP6, as a consequence its removal results in reduced binding of DUSP6 to ERK and sustained ERK phosphorylation that in turn determines increased levels of p21 and p15 and cell-cycle arrest in the G1 phase.
Department of Pharmaceutical and Biomedical Sciences (FARMABIOMED), University of Salerno, Fisciano, Italy.
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Falco
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Festa
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Basile
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Rosati
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Pascale
F
F
Florenzano
S L
SL
Nori
V
V
Nicolin
M
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Di Benedetto
M L
ML
Vecchione
C
C
Arra
A
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Barbieri
V
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De Laurenzi
M C
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Turco
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D059447:Cell Cycle Checkpoints / Q000502:physiology; D002460:Cell Line; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C517035:DUSP6 protein, human; D054642:Dual Specificity Phosphatase 6