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.
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21 June 2004
Article|
June 21 2004
Plexin-B1/RhoGEF–mediated RhoA activation involves the receptor tyrosine kinase ErbB-2
Jakub M. Swiercz,
Jakub M. Swiercz
Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany
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Rohini Kuner,
Rohini Kuner
Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany
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Stefan Offermanns
Stefan Offermanns
Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany
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Jakub M. Swiercz
Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany
Rohini Kuner
Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany
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: [email protected]
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.
Received:
December 11 2003
Accepted:
May 13 2004
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2004
J Cell Biol (2004) 165 (6): 869–880.
Article history
Received:
December 11 2003
Accepted:
May 13 2004
Citation
Jakub M. Swiercz, Rohini Kuner, Stefan Offermanns; Plexin-B1/RhoGEF–mediated RhoA activation involves the receptor tyrosine kinase ErbB-2 . J Cell Biol 21 June 2004; 165 (6): 869–880. doi: https://doi.org/10.1083/jcb.200312094
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