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

Nature Chemical Biology volume 12, pages 117–123 (2016)Cite this article

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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.

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Figure 1: Binding between CypA and CrkII.
Figure 2: Specific interaction between CypA and CrkII in vitro and in vivo.
Figure 3: CypA attenuates CrkII Tyr221 phosphorylation in vitro and in vivo.
Figure 4: CypA attenuates CrkII Tyr221 phosphorylation in MDA-MB-468 cancer cell line.
Figure 5: Effect of the CypA–CrkII complex on cell migration.
Figure 6: Effect of CypA binding to CrkII in integrin signaling.

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Acknowledgements

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.).

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Authors and Affiliations

  1. Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, Minnesota, USA

    Tamjeed Saleh, Paolo Rossi & Charalampos G Kalodimos

  2. Center for Integrative Proteomics Research, Rutgers University, Piscataway, New Jersey, USA

    Tamjeed Saleh, Wojciech Jankowski, Paolo Rossi & Charalampos G Kalodimos

  3. Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA

    Tamjeed Saleh, Wojciech Jankowski, Paolo Rossi, Shreyas Shah, Ki-Bum Lee & Charalampos G Kalodimos

  4. Department of Biochemistry and Molecular Biology, Rutgers New Jersey Medical School, Newark, New Jersey, USA

    Ganapathy Sriram & Raymond B Birge

  5. Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA

    Lissette Alicia Cruz & Alexis J Rodriguez

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  1. Tamjeed Saleh
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Contributions

T.S. and C.G.K. designed the study; T.S. and W.J. recorded and analyzed the NMR data; W.J. and P.R. determined the structure of the complex; T.S., G.S. and R.B.B. collected and analyzed the kinase phosphorylation and cell migration data; T.S., S.S. and K.-B.L. collected and analyzed the FRET and wound healing data; T.S., L.A.C. and A.J.R. collected and analyzed the fluorescence microscopy data; T.S. and C.G.K. wrote the manuscript.

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Correspondence to Charalampos G Kalodimos.

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Saleh, T., Jankowski, W., Sriram, G. et al. Cyclophilin A promotes cell migration via the Abl-Crk signaling pathway. Nat Chem Biol 12, 117–123 (2016). https://doi.org/10.1038/nchembio.1981

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