The tyrosine kinase Syk regulates TPL2 activation signals.
Tpl2/Cot is a serine/threonine kinase that plays a key physiological role in the regulation of immune responses to pro-inflammatory stimuli, including tumor necrosis factor-alpha (TNF-alpha). TNF-alpha stimulates the JNK, ERK, and p38 mitogen-activated protein kinases and the NF-kappaB pathway by recruiting RIP1 and TRAF2 to the TNF receptor 1. Here we showed that Tpl2 activation by TNF-alpha signals depends on the integrity of the Tpl2-interacting proteins RIP1 and TRAF2, which are required for the engagement of the ERK mitogen-activated protein kinase pathway. However, neither RIP1 nor TRAF2 overexpression was sufficient to activate Tpl2 and ERK. We also showed that Tpl2 activation by TNF-alpha depends on a tyrosine kinase activity that is detected in TNF-alpha-stimulated cells. Based on both genetic and biochemical evidence, we concluded that in a variety of cell types, Syk is the tyrosine kinase that plays an important role in the activation of Tpl2 upstream of ERK. These data therefore dissect the TNF receptor 1 proximal events that regulate Tpl2 and ERK and highlight a role for RIP1, TRAF2, and Syk in this pathway.
Eliopoulos
Aristides G
AG
Laboratory of Molecular and Cellular Biology, Division of Basic Sciences, the University of Crete Medical School, Heraklion 71003, Crete, Greece. eliopag@med.uoc.gr
Das
Santasabuj
S
Tsichlis
Philip N
PN
D000818:Animals; D001943:Breast Neoplasms; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D000072377:Syk Kinase; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse