Cyclophilin A promotes cell migration via the Abl-Crk signaling pathway

Tamjeed Saleh, Wojciech Jankowski, Ganapathy Sriram, Paolo Rossi, Shreyas Shah, Ki Bum Lee, Lissette Alicia Cruz, Alexis J. Rodriguez, Raymond B. Birge, Charalampos G. Kalodimos

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Cyclophilin A (CypA) is overexpressed in a number of human cancer types, but the mechanisms by which the protein promotes oncogenic properties of cells are not understood. Here we demonstrate that CypA binds the CrkII adaptor protein and prevents it from switching to the inhibited state. CrkII influences cell motility and invasion by mediating signaling through its SH2 and SH3 domains. CrkII Tyr221 phosphorylation by the Abl or EGFR kinases induces an inhibited state of CrkII by means of an intramolecular SH2-pTyr221 interaction, causing signaling interruption. We show that the CrkII phosphorylation site constitutes a binding site for CypA. Recruitment of CypA sterically restricts the accessibility of Tyr221 to kinases, thereby suppressing CrkII phosphorylation and promoting the active state. Structural, biophysical and in vivo data show that CypA augments CrkII-mediated signaling. A strong stimulation of cell migration is observed in cancer cells wherein both CypA and CrkII are greatly upregulated.

Original languageEnglish (US)
Pages (from-to)117-123
Number of pages7
JournalNature Chemical Biology
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2016

Bibliographical note

Funding Information:
We thank N. Sheth for helping with the cell biological experiments. This work was supported by the US National Institutes of Health (GM80308 to C.G.K. and CA165077 to R.B.B.), the Rutgers University Busch Biomedical Research Grant (to A.J.R.) and the NIH Director''s Innovator Award (1DP20D006462-01 to K.-B.L.).

Funding Information:
We thank N. Sheth for helping with the cell biological experiments. This work was supported by the US National Institutes of Health (GM80308 to C.G.K. and CA165077 to R.B.B.), the Rutgers University Busch Biomedical Research Grant (to A.J.R.) and the NIH Director’s Innovator Award (1DP20D006462-01 to K.-B.L.).

Publisher Copyright:
© 2016 Nature America, Inc.

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