Erbin suppresses the MAP kinase pathway.
We present evidence here that Erbin is a negative regulator of the Ras-Raf-Erk signaling pathway. Expression of Erbin decreases transcription of the AChR epsilon-subunit gene, an event that is mediated by Erk activation. Although it interacts with the ErbB2 C terminus through the PDZ domain, Erbin has no effect on ErbB2 tyrosine phosphorylation or binding to the adaptor proteins Shc and Grb2. In contrast, expression of Erbin greatly impairs activation of Erk, but not Akt, by ligands that activate receptor tyrosine kinases. Moreover, Erbin inhibits the Erk activation by active Ras, while it fails to do so in the presence of active Raf-1. Erbin associates with active Ras, but not inactive Ras nor Raf. Consistently, Erbin interferes with the interaction between Ras and Raf both in vivo and in vitro. Finally, overexpression of Erbin leads to inhibition of NGF-induced neuronal differentiation of PC12 cells, whereas down-regulation of endogenous Erbin by specific siRNA exhibits an opposite effect. Collectively, our study has identified Erbin as a novel suppressor of the Ras signaling by disrupting the Ras-Raf interaction.
Huang
Yang Z
YZ
Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, 35294-0021, USA.
Zang
Mengwei
M
Xiong
Wen C
WC
Luo
Zhijun
Z
Mei
Lin
L
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D051381:Rats; D018631:ras Proteins / Q000037:antagonists & inhibitors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C413364:ERBIN protein, human; D020932:Nerve Growth Factor; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins