The type I interferon receptor mediates tyrosine phosphorylation of the CrkL adaptor protein.
Interferon (IFN) alpha induces rapid and transient tyrosine phosphorylation of the Src homology 2/Src homology 3 (SH2/SH3)-containing CrkL adaptor protein in a time- and dose-dependent manner. Such phosphorylation is most likely regulated by the Type I interferon receptor (IFNR)-associated Tyk-2 kinase, as suggested by the detection of Type I IFN-dependent tyrosine kinase activity in anti-CrkL immunoprecipitates and the IFNalpha-dependent association of CrkL with Tyk-2 in intact cells. Two other Type I IFNs, IFNbeta and IFNomega, also induce tyrosine phosphorylation of CrkL, suggesting that the protein is involved in the signaling pathways of several different Type I IFNs. In the IFNalpha-sensitive U-266 and Daudi cell lines, CrkL interacts via its N terminus SH3 domain with the guanine exchange factor C3G that regulates activation of Rap-1, a small G-protein that exhibits tumor suppressor activity. Thus, tyrosine phosphorylation of CrkL links the functional Type I IFNR complex to the C3G-Rap-1 signaling cascade that mediates growth inhibitory responses.
Ahmad
S
S
Section of Hematology-Oncology, University of Illinois at Chicago and West Side Veterans Administration Hospital, Chicago, Illinois 60607, USA.
Alsayed
Y M
YM
Druker
B J
BJ
Platanias
L C
LC
D048868:Adaptor Proteins, Signal Transducing; D002455:Cell Division; D002460:Cell Line; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology; D008565:Membrane Proteins; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000378:metabolism / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000378:metabolism*; D015398:Signal Transduction; D053634:TYK2 Kinase
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D020662:Guanine Nucleotide Exchange Factors; D007370:Interferon Type I; D016898:Interferon-alpha; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D017471:Receptors, Interferon; C063743:interferon omega 1; D053633:Receptor, Interferon alpha-beta; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human