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Mol. Cell. Biol. 29 (23): 6321-6334

Copyright © 2009 by the American Society for Microbiology. All rights reserved.

Semaphorin 4D Signaling Requires the Recruitment of Phospholipase C{gamma} into the Plexin-B1 Receptor Complex {triangledown}

Jakub M. Swiercz,1,2* Thomas Worzfeld,1,2, and Stefan Offermanns1,2

Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany,1 Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Parkstr. 1, D-61231 Bad Nauheim, Germany2

Received for publication 22 January 2009. Revision received 3 April 2009. Accepted for publication 18 September 2009.

Abstract: The semaphorin 4D (Sema4D) receptor plexin-B1 constitutively interacts with particular Rho guanine nucleotide exchange factors (RhoGEFs) and thereby mediates Sema4D-induced RhoA activation, a process which involves the tyrosine phosphorylation of plexin-B1 by ErbB-2. It is, however, unknown how plexin-B1 phosphorylation regulates RhoGEF activity. We show here that activation of plexin-B1 by Sema4D and its subsequent tyrosine phosphorylation creates docking sites for the SH2 domains of phospholipase C{gamma} (PLC{gamma}). PLC{gamma} is thereby recruited into the plexin-B1 receptor complex and via its SH3 domain activates the Rho guanine nucleotide exchange factor PDZ-RhoGEF. PLC{gamma}-dependent RhoGEF activation is independent of its lipase activity. The recruitment of PLC{gamma} has no effect on the R-Ras GTPase-activating protein activity of plexin-B1 but is required for Sema4D-induced axonal growth cone collapse as well as for the promigratory effects of Sema4D on cancer cells. These data demonstrate a novel nonenzymatic function of PLC{gamma} as an important mechanism of plexin-mediated signaling which links tyrosine phosphorylation of plexin-B1 to the regulation of a RhoGEF protein and downstream cellular processes.

* Corresponding author. Mailing address: Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Parkstr. 1, D-61231 Bad Nauheim, Germany. Phone: 49 (0) 6032 54-705-402. Fax: 49 (0) 6032 54-705-419. E-mail: jakub.swiercz{at}

{triangledown} Published ahead of print on 5 October 2009.

Genetic dissection of plexin signaling in vivo.
T. Worzfeld, J. M. Swiercz, A. Senturk, B. Genz, A. Korostylev, S. Deng, J. Xia, M. Hoshino, J. A. Epstein, A. M. Chan, et al. (2014)
PNAS 111, 2194-2199
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PDZ-RhoGEF and LARG Are Essential for Embryonic Development and Provide a Link between Thrombin and LPA Receptors and Rho Activation.
C. M. Mikelis, T. R. Palmby, M. Simaan, W. Li, R. Szabo, R. Lyons, D. Martin, H. Yagi, S. Fukuhara, H. Chikumi, et al. (2013)
J. Biol. Chem. 288, 12232-12243
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Plexin-B2 Regulates the Proliferation and Migration of Neuroblasts in the Postnatal and Adult Subventricular Zone.
B. Saha, A. R. Ypsilanti, C. Boutin, H. Cremer, and A. Chedotal (2012)
J. Neurosci. 32, 16892-16905
   Abstract »    Full Text »    PDF »
Grb2 mediates semaphorin-4D-dependent RhoA inactivation.
T. Sun, R. Krishnan, and J. M. Swiercz (2012)
J. Cell Sci. 125, 3557-3567
   Abstract »    Full Text »    PDF »

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