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Molecular and Cellular Biology, June 2004, p. 5269-5280, Vol. 24, No. 12
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.12.5269-5280.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Erk/Src Phosphorylation of Cortactin Acts as a Switch On-Switch Off Mechanism That Controls Its Ability To Activate N-WASP

Narcisa Martinez-Quiles,1 Hsin-Yi Henry Ho,2 Marc W. Kirschner,2 Narayanaswamy Ramesh,1,{dagger} and Raif S. Geha1,{dagger}*

Division of Immunology, Children's Hospital,1 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 021152

Received 8 September 2003/ Returned for modification 22 October 2003/ Accepted 11 March 2004

The Arp2/3 complex can be independently activated to initiate actin polymerization by the VCA domain of WASP family members and by the acidic N-terminal and F-actin-binding repeat region of cortactin, which possesses a C-terminal SH3 domain. Cortactin is a target for phosphorylation by Src tyrosine kinases and by serine/threonine kinases that include Erk. Here we demonstrate that cortactin binds N-WASP and WASP via its SH3 domain, induces in vitro N-WASP-mediated actin polymerization, and colocalizes with N-WASP and WASP at sites of active actin polymerization. Erk phosphorylation and a mimicking S405,418D double mutation enhanced cortactin binding and activation of N-WASP. In contrast, Src phosphorylation inhibited the ability of cortactin previously phosphorylated by Erk, and that of S405,418D double mutant cortactin, to bind and activate N-WASP. Furthermore, Y->D mutation of three tyrosine residues targeted by Src (Y421, Y466, and Y482) inhibited the ability of S405,418D cortactin to activate N-WASP. We propose that Erk phosphorylation liberates the SH3 domain of cortactin from intramolecular interactions with proline-rich regions, causing it to synergize with WASP and N-WASP in activating the Arp2/3 complex, and that Src phosphorylation terminates cortactin activation of N-WASP and WASP.

* Corresponding author. Mailing address: Division of Immunology, Children's Hospital, One Blackfan Circle, NRB, 10th floor, Boston, MA 02115. Phone: (617) 919-2482. Fax: (617) 730-0528. E-mail: raif.geha{at}childrens.harvard.edu.

{dagger} N.R. and R.S.G. contributed equally to this work.

Molecular and Cellular Biology, June 2004, p. 5269-5280, Vol. 24, No. 12
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.12.5269-5280.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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