Pyk2 regulates cell-edge protrusion dynamics by interacting with Crk |
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Authors: | Nikola Lukic Stefanie Lapetina Hanna Grobe Kolluru D. Srikanth Shams Twafra Jonathan Solomon Tal Sneh Michal Gendler Ronen Zaidel-Bar Hava Gil-Henn |
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Affiliation: | University of Wisconsin, Madison;aLaboratory for Cell Migration and Invasion, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed 1311502, Israel;bDepartment of Cell and Developmental Biology, Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel |
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Abstract: | Focal adhesion kinase (FAK) is well established as a regulator of cell migration, but whether and how the closely related proline-rich tyrosine kinase 2 (Pyk2) regulates fibroblast motility is still under debate. Using mouse embryonic fibroblasts (MEFs) from Pyk2–/– mice, we show here, for the first time, that lack of Pyk2 significantly impairs both random and directed fibroblast motility. Pyk2–/– MEFs show reduced cell-edge protrusion dynamics, which is dependent on both the kinase and protein–protein binding activities of Pyk2. Using bioinformatics analysis of in vitro high- throughput screens followed by text mining, we identified CrkI/II as novel substrates and interactors of Pyk2. Knockdown of CrkI/II shows altered dynamics of cell-edge protrusions, which is similar to the phenotype observed in Pyk2–/– MEFs. Moreover, epistasis experiments suggest that Pyk2 regulates the dynamics of cell-edge protrusions via direct and indirect interactions with Crk that enable both activation and down-regulation of Crk-mediated cytoskeletal signaling. This complex mechanism may enable fine-tuning of cell-edge protrusion dynamics and consequent cell migration on the one hand together with tight regulation of cell motility, a process that should be strictly limited to specific time and context in normal cells, on the other hand. |
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