ErbB-2 and Met Reciprocally Regulate Cellular Signaling via Plexin-B1*

  1. Jakub M. Swiercz 1 ,
  2. Thomas Worzfeld 1 and
  3. Stefan Offermanns 2
  1. Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
  1. 2 To whom correspondence should be addressed. Tel.: 49-6221-548246; Fax: 49-6221-548549; E-mail: stefan.offermanns{at}pharma.uni-heidelberg.de.

Abstract

Sema4D-induced activation of plexin-B1 has been reported to evoke different and sometimes opposing cellular responses. The mechanisms underlying the versatility of plexin-B1-mediated effects are not clear. Plexin-B1 can associate with the receptor tyrosine kinases ErbB-2 and Met. Here we show that Sema4D-induced activation and inactivation of RhoA require ErbB-2 and Met, respectively. In breast carcinoma cells, Sema4D can have pro- and anti-migratory effects depending on the presence of ErbB-2 and Met, and the exchange of the two receptor tyrosine kinases is sufficient to convert the cellular response to Sema4D from pro- to anti-migratory and vice versa. This work identifies a novel mechanism by which plexin-mediated signaling can be regulated and explains how Sema4D can exert different biological activities through the differential association of its receptor with ErbB-2 and Met.

Footnotes

  • 3 The abbreviations used are: GAP, GTPase-activating protein; VSV, vesicular stomatitis virus; siRNA, small interfering RNA; GST, glutathione S-transferase; FBS, fetal bovine serum.

  • * The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Graphic The on-line version of this article (available at ) contains supplemental Figs. S1 and S2.

  • 1 Recipients of a postdoctoral scholarship of the Medical Faculty Heidelberg.

    • Received August 16, 2007.
    • Revision received November 8, 2007.
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