IFN-γ Activates the C3G/Rap1 Signaling Pathway

  • Alsayed Y
  • Uddin S
  • Ahmad S
  • et al.
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Abstract

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.

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APA

Alsayed, Y., Uddin, S., Ahmad, S., Majchrzak, B., Druker, B. J., Fish, E. N., & Platanias, L. C. (2000). IFN-γ Activates the C3G/Rap1 Signaling Pathway. The Journal of Immunology, 164(4), 1800–1806. https://doi.org/10.4049/jimmunol.164.4.1800

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