Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP

Narcisa Martinez-Quiles, Hsin-Yi Henry Ho, Marc W. Kirschner, Narayanaswamy Ramesh, Raif S. Geha

Research output: Contribution to journalArticle

210 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5269-5280
Number of pages12
JournalMolecular and Cellular Biology
Volume24
Issue number12
DOIs
StatePublished - Jun 2004
Externally publishedYes

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Cortactin
Aptitude
Phosphorylation
src Homology Domains
Actins
Actin-Related Protein 2-3 Complex
Polymerization
Mutation
src-Family Kinases
Protein-Serine-Threonine Kinases
Proline
Tyrosine
Catalytic Domain

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. / Martinez-Quiles, Narcisa; Ho, Hsin-Yi Henry; Kirschner, Marc W.; Ramesh, Narayanaswamy; Geha, Raif S.

In: Molecular and Cellular Biology, Vol. 24, No. 12, 06.2004, p. 5269-5280.

Research output: Contribution to journalArticle

Martinez-Quiles, Narcisa ; Ho, Hsin-Yi Henry ; Kirschner, Marc W. ; Ramesh, Narayanaswamy ; Geha, Raif S. / Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. In: Molecular and Cellular Biology. 2004 ; Vol. 24, No. 12. pp. 5269-5280.
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