IFN-gamma activates the C3G/Rap1 signaling pathway.
IFN-gamma transduces signals by activating the IFN-gamma 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-gamma 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-gamma, 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-gamma-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-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 cells 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 differentially regulated by different IFN subtypes. Taken altogether, our data demonstrate that, in addition to activating the Stat pathway, IFN-gamma activates a distinct signaling cascade that may play an important role in the generation of its growth inhibitory effects on target cells.
Alsayed
Y
Y
Section of Hematology-Oncology, University of Illinois at Chicago 60607, USA.
Uddin
S
S
Ahmad
S
S
Majchrzak
B
B
Druker
B J
BJ
Fish
E N
EN
Platanias
L C
LC
D048868:Adaptor Proteins, Signal Transducing; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases; D018909:src Homology Domains / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D020735:Guanine Nucleotide-Releasing Factor 2; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; C067419:CBL protein, human