IFN-gamma activates the C3G/Rap1 signaling pathway

Citation
Y. Alsayed et al., IFN-gamma activates the C3G/Rap1 signaling pathway, J IMMUNOL, 164(4), 2000, pp. 1800-1806
Citations number
54
Categorie Soggetti
Immunology
Journal title
JOURNAL OF IMMUNOLOGY
ISSN journal
00221767 → ACNP
Volume
164
Issue
4
Year of publication
2000
Pages
1800 - 1806
Database
ISI
SICI code
0022-1767(20000215)164:4<1800:IATCSP>2.0.ZU;2-U
Abstract
IFN-gamma transduces signals by activating the IFN-gamma receptor-associate d Jak-1 and Jak-2 kinases and by inducing tyrosine phosphorylation and acti vation of the Stat-1 transcriptional activator. We report that IFN-gamma ac tivates a distinct signaling cascade involving the c-cbl protooncogene prod uct, CrkL adapter, and small G protein Rap1, During treatment of NB-4 human cells with IFN-gamma, c-cbl protooncogene product is rapidly phosphorylate d on tyrosine and provides a docking site for the src homology 2 domain of CrkL, which also undergoes IFN-gamma-dependent tyrosine phosphorylation, Cr kL 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-gamma-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 cel ls with type I IFNs (IFN-alpha, IFN-beta), which also engage CrkL in their signaling pathways. On the other hand, IFN-gamma does not induce formation of nuclear CrkL-Stat5 DNA-binding complexes, which are induced by IFN-alpha and IFN-beta, indicating that pathways downstream of CrkL are differential ly regulated by different IFN subtypes, Taken altogether, our data demonstr ate that, in addition to activating the Stat pathway, IFN-gamma activates a distinct signaling cascade that may play an important role in the generati on of its growth inhibitory effects on target cells.