Erbin is a negative modulator of cardiac hypertrophy.
ErbB2 interacting protein (Erbin) is a widely expressed protein and participates in inhibition of several intracellular signaling pathways. Its mRNA has been found to be present in relatively high levels in the heart. However, its physiological role in the heart has not been explored. In the present work, we elucidated the role of Erbin in cardiac hypertrophy. Cardiac hypertrophy was induced in mice either by isoproterenol administration or by aortic constriction. The level of Erbin was significantly decreased in both models. Erbin(-/-) mice rapidly develop decompensated cardiac hypertrophy, and following severe pressure overload all Erbin(-/-) mice died from heart failure. Down-regulation of Erbin expression was also observed in biopsies derived from human failing hearts. It is known that Erbin inhibits Ras-mediated activation of the extracellular signal-regulated kinase (ERK) by binding to Soc-2 suppressor of clear homolog (Shoc2). Our data clearly show that ERK phosphorylation is enhanced in the heart tissues of Erbin(-/-) mice. Furthermore, we clearly demonstrate here that Erbin associates with Shoc2 in both whole hearts and in cardiomyocytes, and that in the absence of Erbin, Raf is phosphorylated and binds Shoc2, resulting in ERK phosphorylation. In conclusion, Erbin is an inhibitor of pathological cardiac hypertrophy, and this inhibition is mediated, at least in part, by modulating ERK signaling.
Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem 91120, Israel.
Inbal
I
Rachmin
Sagi
S
Tshori
Yoav
Y
Smith
Amit
A
Oppenheim
Sylvie
S
Marchetto
Gillian
G
Kay
Roger S-Y
RS
Foo
Noa
N
Dagan
Eliahu
E
Golomb
Dan
D
Gilon
Jean-Paul
JP
Borg
Ehud
E
Razin
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011312:Pressure
D015415:Biomarkers; D002352:Carrier Proteins; C498804:Erbb2ip protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D007545:Isoproterenol