Erbin Suppresses the MAP Kinase Pathway

Abstract

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 ⑀-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 downregulation 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.Extracellular signal-regulated kinases (Erk) 1 are a subfamily of mitogen-activated protein kinases (MAPK) that play important roles in a great array of cell programs including proliferation, differentiation, and apoptosis (1, 2). As exemplified by binding to growth factors such as EGF, receptor tyrosine kinases are activated and undergo autophosphorylation on tyrosine residues (3, 4). Phosphorylated tyrosine residues recruit adaptor proteins to the plasma membrane by directly interacting with modules including Src homology 2 (SH2) or phosphotyrosine binding domain (PTB). Grb2, one of such adaptors, brings guanyl nucleotide exchange factor (SOS) to the plasma membrane in proximity with Ras and expedites exchange of GDP for GTP on Ras (5). Activated Ras (GTP-bound) then directly binds to Raf and allows the latter to be activated (1, 6). Active Raf triggers sequential activation of MEK, a MAPK kinase, and Erk, leading to phosphorylation of various regulatory proteins including nuclear transcription factors such as Elk-1 and Myc as well as many cytoplasmic proteins (7, 8).In the past, extensive efforts have been made to identify factors that participate in regulation of the Ras-Raf-Erk pathway. Several modulators have been identified that positively influence the pathway at different levels. For example, the MEK partner 1 (MP1) was isolated as a binding protein that interacts with both MEK1 and Erk1 to enhance the efficiency of Erk phosphorylation by MEK (9). A second protein is the kinase suppressor of Ras (KSR) that is believed to act as a scaffold for Raf-1, MEK, and Erk (10). The Connector enhancer of KSR (CNK) directly binds to Raf and is involved in activation of the Raf/MEK/Erk pathway (11). Sur-8 is an interesting protein that contains multiple leucine-rich repeats (LRRs) (12) and binds to both Ras and Raf-1. Although Ras can directly associates with Raf upon activation, the presence of Sur-8 increase...

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