Immunophilins control T lymphocyte adhesion and migration by regulating CrkII binding to C3G

Pulak Ranjan Nath, Guangyu Dong, Alex Braiman, Noah Isakov

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Crk adaptor proteins are key players in signal transduction from a variety of cell surface receptors. CrkI and CrkII, the two alternative spliced forms of CRK, possess an N-terminal Src homology 2 domain, followed by a Src homology 3 (SH3) domain, whereas CrkII possesses in addition a C-terminal linker region plus a SH3 domain, which operate as regulatory moieties. In this study, we investigated the ability of immunophilins, which function as peptidyl-prolyl isomerases, to regulate Crk proteins in human T lymphocytes. We found that endogenous CrkII, but not CrkI, associates with the immunophilins, cyclophilin A, and 12- kDa FK506-binding protein, in resting human Jurkat T cells. In addition, cyclophilin A increased Crk SH3 domain-binding guanine-nucleotide releasing factor (C3G) binding to CrkII, whereas inhibitors of immunophilins, such as cyclosporine A (CsA) and FK506, inhibited CrkII, but not CrkI association with C3G. Expression in Jurkat T cells of phosphorylation indicator of Crk chimeric unit plasmid, a plasmid encoding the human CrkII1-236 sandwiched between cyan fluorescent protein and yellow fluorescent protein, demonstrated a basal level of fluorescence resonance energy transfer, which increased in response to cell treatment with CsA and FK506, reflecting increased trans-to-cis conversion of CrkII. Crk-C3G complexes are known to play an important role in integrin-mediated cell adhesion and migration. We found that overexpression of CrkI or CrkII increased adhesion and migration of Jurkat T cells. However, immunophilin inhibitors suppressed the ability of CrkII- but not CrkIoverexpressing cells to adhere to fibronectin-coated surfaces and migrate toward the stromal cell-derived factor 1a chemokine. The present data demonstrate that immunophilins regulate CrkII, but not CrkI activity in T cells and suggest that CsA and FK506 inhibit selected effector T cell functions via a CrkII-dependent mechanism.

Original languageEnglish
Pages (from-to)3966-3977
Number of pages12
JournalJournal of Immunology
Issue number8
StatePublished - 15 Oct 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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