The rasGAP‐binding protein, Dok‐1, mediates activin signaling via serine/threonine kinase receptors

Activins, members of the transforming growth factor‐β 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.