Actin depolymerization-induced tyrosine phosphorylation of cortactin: the role of Fer kinase

Biochem J. 2004 Jun 1;380(Pt 2):581-91. doi: 10.1042/BJ20040178.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / chemistry
  • Actins / metabolism*
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • CHO Cells
  • Cortactin
  • Cricetinae
  • Enzyme Activation / drug effects
  • Microfilament Proteins / metabolism*
  • Osmotic Pressure
  • Peptides / chemistry
  • Peptides / metabolism
  • Phosphorylation
  • Phosphotyrosine
  • Polymers / metabolism*
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-fyn
  • Thiazoles / pharmacology
  • Thiazolidines
  • Transfection / methods
  • Tyrosine / metabolism*


  • Actins
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cortactin
  • Microfilament Proteins
  • Peptides
  • Polymers
  • Proto-Oncogene Proteins
  • Thiazoles
  • Thiazolidines
  • proto-oncogene protein c-fes-fps
  • Phosphotyrosine
  • Tyrosine
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-fyn
  • latrunculin B