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Molecular and Cellular Biology, December 2009, p. 6321-6334, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00103-09
Copyright © 2009, 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 22 January 2009/ Returned for modification 3 April 2009/ Accepted 18 September 2009

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}mpi-bn.mpg.de

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

Molecular and Cellular Biology, December 2009, p. 6321-6334, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00103-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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