Mediation by the protein-tyrosine kinase Tec of signaling between the B cell antigen receptor and Dok-1.
A variety of growth factor receptors induce the tyrosine phosphorylation of a nonreceptor protein-tyrosine kinase Tec as well as that of a Tec-binding protein of 62 kDa. Given the similarity in properties between this 62-kDa protein and p62(Dok-1), the possibility that these two proteins are identical was investigated. Overexpression of a constitutively active form of Tec in a pro-B cell line induced the hyperphosphorylation of endogenous Dok-1. Tec also associated with Dok-1 in a phosphorylation-dependent manner in 293 cells. Tec mediated marked phosphorylation of Dok-1 both in vivo and in vitro, and this effect required both the Tec homology and Src homology 2 domains of Tec in addition to its kinase activity. Expression of Dok-1 in 293 cells induced inhibition of Ras activity, suggesting that Dok-1 is a negative regulator of Ras. In the immature B cell line Ramos, cross-linking of the B cell antigen receptor (BCR) resulted in tyrosine phosphorylation of Dok-1, and this effect was markedly inhibited by expression of dominant negative mutants of Tec. Furthermore, overexpression of Dok-1 inhibited activation of the c-fos promoter induced by stimulation of the BCR. These results suggest that Tec is an important mediator of signaling from the BCR to Dok-1.
Yoshida
K
K
Division of Functional Genomics, Departments of Hematology and Cardiology, Jichi Medical School, Kawachi-gun, Tochigi 329-0498, Japan.
Yamashita
Y
Y
Miyazato
A
A
Ohya
K
K
Kitanaka
A
A
Ikeda
U
U
Shimada
K
K
Yamanaka
T
T
Ozawa
K
K
Mano
H
H
D001402:B-Lymphocytes; D002051:Burkitt Lymphoma; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D016601:RNA-Binding Proteins; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers; D020703:ras GTPase-Activating Proteins / Q000378:metabolism; D018909:src Homology Domains
D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C074561:GAP-associated protein p62; C490412:NR4A3 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D011947:Receptors, Antigen, B-Cell; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D020703:ras GTPase-Activating Proteins