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J. Cell Biol. 165 (6): 869-880

Copyright © 2004 by the Rockefeller University Press.

Article

Plexin-B1/RhoGEF–mediated RhoA activation involves the receptor tyrosine kinase ErbB-2

Jakub M. Swiercz, Rohini Kuner, , and Stefan Offermanns

Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany

Address correspondence to Stefan Offermanns, Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Tel.: 49-6221-54-8246/7. Fax: 49-6221-54-8549. email: Stefan.Offermanns{at}urz.uni-heidelberg.de

Abstract: Plexins are widely expressed transmembrane proteins that mediate the effects of semaphorins. The molecular mechanisms of plexin-mediated signal transduction are still rather unclear. Plexin-B1 has recently been shown to mediate activation of RhoA through a stable interaction with the Rho guanine nucleotide exchange factors PDZ-RhoGEF and LARG. However, it is unclear how the activity of plexin-B1 and its downstream effectors is regulated by its ligand Sema4D. Here, we show that plexin-B family members stably associate with the receptor tyrosine kinase ErbB-2. Binding of Sema4D to plexin-B1 stimulates the intrinsic tyrosine kinase activity of ErbB-2, resulting in the phosphorylation of both plexin-B1 and ErbB-2. A dominant-negative form of ErbB-2 blocks Sema4D-induced RhoA activation as well as axonal growth cone collapse in primary hippocampal neurons. Our data indicate that ErbB-2 is an important component of the plexin-B receptor system and that ErbB-2–mediated phosphorylation of plexin-B1 is critically involved in Sema4D-induced RhoA activation, which underlies cellular phenomena downstream of plexin-B1, including axonal growth cone collapse.

Key Words: semaphorins; axonal growth cone; Erk; tyrosine phosphorylation

The online version of this article includes supplemental material.

Abbreviations used in this paper: HEK, human embryonic kidney; His, histidine; LARG, leukemia-associated RhoGEF; OTK, off-track; PDZ, PSD-95/DIg/Z0-1; VSV, vesicular stomatitis virus glycoprotein.

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