Pyk2 regulates cell-edge protrusion dynamics by interacting with Crk

Nikola Lukic, Stefanie Lapetina, Hanna Grobe, Kolluru D. Srikanth, Shams Twafra, Jonathan Solomon, Tal Sneh, Michal Gendler, Ronen Zaidel-Bar, Hava Gil-Henn

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number0640
JournalMolecular Biology of the Cell
Volume32
Issue number21
DOIs
StatePublished - 1 Nov 2021

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