The rasGAP-binding protein, Dok-1, mediates activin signaling via serine/threonine kinase receptors.
Activins, members of the transforming growth factor-beta family, are pleiotropic growth and differentiation factors. Activin A induces B-cell apoptosis. To identify the genes responsible for activin-induced apoptosis, we performed retrovirus-mediated gene trap screening in a mouse B-cell line. We identified the rasGAP-binding protein Dok-1 (p62) as an essential molecule that links activin receptors with Smad proteins. In B cells overexpressing Dok-1, activin A-induced apoptotic responses were augmented. The expression of bcl-X(L) was down-regulated by inhibition of the ras/Erk pathway. Activin stimulation triggered association of Dok-1 with Smad3, as well as association of Smad3 with Smad4. Dok-1 also associated with both the type I and type II activin receptors. Dok-1 has been characterized previously as a tyrosine-phosphorylated protein acting downstream of the protein tyrosine kinase pathway: intriguingly, activin signaling did not induce tyrosine phosphorylation of Dok-1. These findings indicate that Dok-1 acts as an adaptor protein that links the activin receptors with the Smads, suggesting a novel function for Dok-1 in activin signaling leading to B-cell apoptosis.
Yamakawa
Norio
N
Institute for Enzyme Research, The University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
Tsuchida
Kunihiro
K
Sugino
Hiromu
H
D030201:Activin Receptors, Type I / Q000378:metabolism*; D030301:Activin Receptors, Type II / Q000378:metabolism*; D028341:Activins / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D028322:Inhibin-beta Subunits / Q000494:pharmacology; D019169:Jurkat Cells; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C489561:Dok1 protein, mouse; C074561:GAP-associated protein p62; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; C422405:activin A; D020703:ras GTPase-Activating Proteins; D028341:Activins; D014443:Tyrosine; D028322:Inhibin-beta Subunits; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; D018631:ras Proteins