Hgs (Hrs), a FYVE domain protein, is involved in Smad signaling through cooperation with SARA

Smad proteins are effector molecules that transmit signals from the recepto rs for the transforming growth factor beta (TGF-beta) superfamily to the nu cleus; of the Smad proteins, Smad2 and Smad4 are essential components for m ouse early embryogenesis. We demonstrated that Hgs, a FYVE domain protein, binds to Smad2 in its C-terminal half and cooperates with another FYVE doma in protein, the Smad anchor for receptor activation (SARA), to stimulate ac tivin receptor-mediated signaling through efficient recruitment of Smad2 to the receptor. Furthermore, a LacZ knock-in allele of the C-terminal half-d eletion mutant of mouse Hgs was created by gene targeting. The introduced m utation causes an embryonic lethality between embryonic days 8.5 and 10.5. Mutant cells showed significantly decreased responses to stimulation with a ctivin and TGF-beta. These findings suggest that the two FYVE domain protei ns, Hgs and SARA, are prerequisites for receptor-mediated activation of Sma d2.