The F-actin-binding protein cortactin is an important regulator of cytoskeletal dynamics, and a prominent target of various tyrosine kinases. Tyrosine phosphorylation of cortactin has been suggested to reduce its F-actin cross-linking capability. In the present study, we investigated whether a reciprocal relationship exists, i.e. whether the polymerization state of actin impacts on the cortactin tyrosine phosphorylation. Actin depolymerization by LB (latrunculin B) induced robust phosphorylation of C-terminal tyrosine residues of cortactin. In contrast, F-actin stabilization by jasplakinolide, which redistributed cortactin to F-actin-containing patches, prevented cortactin phosphorylation triggered by hypertonic stress or LB. Using cell lines deficient in candidate tyrosine kinases, we found that the F-actin depolymerization-induced cortactin phosphorylation was mediated by the Fyn/Fer kinase pathway, independent of Src and c-Abl. LB caused modest Fer activation and strongly facilitated the association between Fer and cortactin. Interestingly, the F-actin-binding region within the cortactin N-terminus was essential for the efficient phosphorylation of C-terminal tyrosine residues. Investigating the structural requirements for the Fer–cortactin association, we found that (i) phosphorylation-incompetent cortactin still bound to Fer; (ii) the isolated N-terminus associated with Fer; and (iii) the C-terminus alone was insufficient for binding. Thus the cortactin N-terminus participates in the Fer–cortactin interaction, which cannot be fully due to the binding of the Fer Src homology 2 domain to C-terminal tyrosine residues of cortactin. Taken together, F-actin stabilization prevents cortactin tyrosine phosphorylation, whereas depolymerization promotes it. Depolymerization-induced phosphorylation is mediated by Fer, and requires the actin-binding domain of cortactin. These results define a novel F-actin-dependent pathway that may serve as a feedback mechanism during cytoskeleton remodelling.
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Research Article|
June 01 2004
Actin depolymerization-induced tyrosine phosphorylation of cortactin: the role of Fer kinase
Lingzhi FAN;
Lingzhi FAN
*Department of Surgery, The Toronto General Hospital and University Health Network, 200 Elizabeth Street, Toronto, ON, Canada M5G 2C4
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Caterina Di CIANO-OLIVEIRA;
Caterina Di CIANO-OLIVEIRA
*Department of Surgery, The Toronto General Hospital and University Health Network, 200 Elizabeth Street, Toronto, ON, Canada M5G 2C4
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Scott A. WEED;
Scott A. WEED
†Department of Craniofacial Biology and Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, U.S.A.
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Andrew W. B. CRAIG;
Andrew W. B. CRAIG
‡Department of Biochemistry, Queen's University, Kingston, ON, Canada K7L 3N6
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Peter A. GREER;
Peter A. GREER
‡Department of Biochemistry, Queen's University, Kingston, ON, Canada K7L 3N6
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Ori D. ROTSTEIN;
Ori D. ROTSTEIN
*Department of Surgery, The Toronto General Hospital and University Health Network, 200 Elizabeth Street, Toronto, ON, Canada M5G 2C4
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András KAPUS
András KAPUS
1
*Department of Surgery, The Toronto General Hospital and University Health Network, 200 Elizabeth Street, Toronto, ON, Canada M5G 2C4
1To whom correspondence should be addressed (e-mail akapus@uhnres.utoronto.ca).
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Biochem J (2004) 380 (2): 581–591.
Article history
Received:
February 02 2004
Revision Received:
March 16 2004
Accepted:
March 19 2004
Accepted Manuscript online:
March 19 2004
Citation
Lingzhi FAN, Caterina Di CIANO-OLIVEIRA, Scott A. WEED, Andrew W. B. CRAIG, Peter A. GREER, Ori D. ROTSTEIN, András KAPUS; Actin depolymerization-induced tyrosine phosphorylation of cortactin: the role of Fer kinase. Biochem J 1 June 2004; 380 (2): 581–591. doi: https://doi.org/10.1042/bj20040178
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