Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 14, Issue 8, Pages 3216-3229Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.e02-11-0753
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Funding
- NCI NIH HHS [P01 CA040042, R37 CA029243, CA-40042, CA-29243, R01 CA029243] Funding Source: Medline
- NIDCR NIH HHS [K22 DE014364, DE14364] Funding Source: Medline
- NIGMS NIH HHS [R01 GM038542, GM-38542] Funding Source: Medline
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Cortactin is an F-actin binding protein that activates actin-related protein 2/3 complex and is localized within lamellipodia. Cortactin is a substrate for Src and other protein tyrosine kinases involved in cell motility, where its phosphorylation. on tyrosines 421, 466, and 482 in the carboxy terminus is required for cell movement and metastasis. In spite of the importance of cortactin tyrosine phosphorylation in cell motility, little is known regarding the structural, spatial. or signaling requirements regulating cortactin tyrosine phosphorylation. Herein, we report that phosphorylation of cortactin tyrosine residues in the carboxy terminus requires the amino-terminal domain and Rac1-mediated localization to the cell periphery. Phosphorylation-specific antibodies directed against tyrosine 421 and 466 were produced to study the regulation and localization of tyrosine phosphorylated cortactin. Phosphorylation. of cortactin tyrosine 421 and 466 was elevated in response to Src, epidermal growth factor receptor and Rac1 activation, and tyrosine 421 phosphorylated cortactin localized with F-actin in lamellipodia and podosomes. Cortactin tyrosine phosphorylation is progressive, with tyrosine 421 phosphorylation required for phosphorylation. of tyrosine 466. These results indicate that cortactin tyrosine phosphorylation requires Rac1-induced cortactin targeting to cortical actin networks, where it is tyrosine phosphorylated in hierarchical manner that is closely coordinated with its ability to regulate actin dynamics.
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