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PMID:15169891

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Citation

Martinez-Quiles, N, Ho, HY, Kirschner, MW, Ramesh, N and Geha, RS (2004) Erk/Src phosphorylation of cortactin acts as a switch on-switch off mechanism that controls its ability to activate N-WASP. Mol. Cell. Biol. 24:5269-80

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.

Links

PubMed PMC419870 Online version:10.1128/MCB.24.12.5269-5280.2004

Keywords

Actin-Related Protein 2; Actin-Related Protein 3; Actins/metabolism; Animals; Binding Sites; Cell Line; Cortactin; Cytoskeletal Proteins/metabolism; Humans; Jurkat Cells; Mice; Microfilament Proteins/chemistry; Microfilament Proteins/genetics; Microfilament Proteins/metabolism; Mitogen-Activated Protein Kinases/metabolism; Mutagenesis, Site-Directed; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Phosphorylation; Proteins/metabolism; Recombinant Fusion Proteins/chemistry; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Swiss 3T3 Cells; Wiskott-Aldrich Syndrome Protein; Wiskott-Aldrich Syndrome Protein, Neuronal; src Homology Domains; src-Family Kinases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:WASL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q60598

F

Seeded From UniProt

complete

HUMAN:WASP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q14247

F

Seeded From UniProt

complete

HUMAN:SRC8

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P42768

F

Seeded From UniProt

complete

MOUSE:SRC8

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O08816

F

Seeded From UniProt

complete

MOUSE:SRC8

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q91YD9

F

Seeded From UniProt

complete

MOUSE:SRC8

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q95107

F

Seeded From UniProt

complete

MOUSE:WASL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q60598

F

Seeded From UniProt

complete

BOVIN:WASL

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q60598

F

Seeded From UniProt

complete


See also

References

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