IFN-γ activates the C3G/Rap1 signaling pathway

Yazan Alsayed, Shahab Uddin, Sarfraz Ahmad, Beata Majchrzak, Brian J. Druker, Eleanor N. Fish, Leonidas C. Platanias

Research output: Contribution to journalArticlepeer-review

63 Scopus citations


IFN-γ, transduces signals by activating the IFN-γ, receptor-associated Jak-1 and Jak-2 kinases and by inducing tyrosine phosphorylation and activation of the Stat-1 transcriptional activator. We report that IFN-γ activates a distinct signaling cascade involving the c-cbl protooncogene product, CrkL adapter, and small G protein Rap1. During treatment of NB-4 human cells with IFN-γ, c-cbl protooncogene product is rapidly phosphorylated on tyrosine and provides a docking site for the src homology 2 domain of CrkL, which also undergoes IFN-γ-dependent tyrosine phosphorylation. CrkL then regulates activation of the guanine exchange factor C3G, with which it interacts constitutively via its N terminus src homology 3 domain. This results in the IFN-γ-dependent activation of Rap1, a protein known to exhibit tumor suppressor activity and mediate growth inhibitory responses. In a similar manner, Rap1 is also activated in response to treatment of cells with type I IFNs (IFN-α, IFN-β), which also engage CrkL in their signaling pathways. On the other hand, IFN-γ, does not induce formation of nuclear CrkL-Stat5 DNA-binding complexes, which are induced by IFN-α and IFN-β, indicating that pathways downstream of CrkL are differentially regulated by different IFN subtypes. Taken altogether, our data demonstrate that, in addition to activating the Stat pathway, IFN-γ activates a distinct signaling cascade that may play an important role in the generation of its growth inhibitory effects on target cells.

Original languageEnglish (US)
Pages (from-to)1800-1806
Number of pages7
JournalJournal of Immunology
Issue number4
StatePublished - Feb 15 2000

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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