Dok protein family members are involved in signaling mediated by the type 1 Fcepsilon receptor.
Aggregation of type 1 Fcepsilon receptors (FcepsilonRI) on mast cells activates a biochemical cascade that culminates in secretion of inflammatory mediators, as well as in changes of cell morphology and adhesion properties. Some of the intracellular components involved in the early coupling events are still unidentified. Here we show that two adaptor proteins, downstream of tyrosine kinases (Dok)-1 and Dok-2, are involved in the FcepsilonRI coupling cascade in the rat mucosal-type mast cells of the RBL-2H3 line. Dok-1 is found to be constitutively associated with the FcepsilonRI, even in untreated cells, and this interaction is not affected by this receptor's aggregation. Both Dok forms undergo a fast and relatively long-term tyrosyl-phosphorylation. This modification of Dok-1 increases its association with RasGAP, suggesting that it is modulating Ras activity. Indeed, we further found that FcepsilonRI-mediated Ras/Raf1/Erk signaling as well as the de novo synthesis of TNF-alpha are markedly reduced in cells overexpressing Dok-1. Moreover, FcepsilonRI clustering causes both Dok-1 and Dok-2 to become docking sites for other signaling molecules including Nck, CrkL and Cas. The latter proteins have been implicated particularly in regulation of the actin-cytoskeletal reorganization. Hence Dok-1/Dok-2 may also be involved in the FcepsilonRI-stimulated processes of cytoskeleton rearrangement required for cell adhesion, membrane ruffling and exocytosis.
Abramson
Jakub
J
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Rozenblum
Guido
G
Pecht
Israel
I
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D017455:Receptors, IgE / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C115089:DOK2 protein, human; C074561:GAP-associated protein p62; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)