A kinase independent function for Tec kinase ITK in regulating antigen receptor induced serum response factor activation.
The Tec family kinases are critical downstream regulators of antigen receptor signals in lymphocytes. As kinases, they act on critical substrates to regulate signals such as calcium increase leading to activation of transcription factors such as NFAT, NFkappaB and SRF. We now show here that ITK, a member of the Tec family of tyrosine kinases, has a kinase independent function. Mutants of ITK that lack kinase activity or a kinase domain can rescue cells lacking Tec family kinases for antigen receptor induced SRF activation, but not for NFAT, AP-1 or NFkappaB activation. Furthermore, expression of these mutants in WT cells enhanced SRF activation. This kinase independent function required the SH2 domain since a mutant lacking both the kinase and SH2 domains was much less effective at rescuing SRF activation. This kinase-deleted mutant could partially rescue ERK activation, and interact with multiple tyrosine phosphorylated proteins during antigen receptor signaling, suggesting that ITK uses a scaffolding function that regulates signals leading to specific regulation of SRF activation.
Hao
Shengli
S
Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, 115 Henning Building, University Park, 16802, USA.
Qi
Qian
Q
Hu
Jianfang
J
August
Avery
A
D000818:Animals; D002417:Cattle; D002460:Cell Line; D002645:Chickens; D004789:Enzyme Activation; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011946:Receptors, Antigen / Q000378:metabolism*; D026362:Serum Response Factor / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism
D016328:NF-kappa B; D050778:NFATC Transcription Factors; D011946:Receptors, Antigen; D026362:Serum Response Factor; D018808:Transcription Factor AP-1; D019000:Phosphotyrosine; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases