OPPOSING BMP AND EGF SIGNALING PATHWAYS CONVERGE ON THE TGF-BETA FAMILY MEDIATOR SMAD1

The growth factor TGF-beta, bone morphogenetic proteins (BMPs) and rel ated factors regulate cell proliferation, differentiation and apoptosi s, controlling the development and maintenance of most tissues(1,2). T heir signals are transmitted through the phosphorylation of the tumour -suppressor SMAD proteins by receptor protein serine/threonine kinases (RS/TKs)(3-10), leading to the nuclear accumulation(5,9,11,12) and tr anscriptional activity of SMAD proteins(6,12,13). Here we report that Smad1, which mediates BMP signals, is also a target of mitogenic growt h-factor signalling through epidermal growth factor and hepatocyte gro wth factor receptor protein tyrosine kinases (RTKs). Phosphorylation o ccurs at specific serines within the region linking the inhibitory and effector domains of Smad1, and is catalysed by the Erk family of mito gen-activated protein kinases. In contrast to the BMP-stimulated phosp horylation of Smad1, which affects carboxy-terminal serines and induce s nuclear accumulation of Smad1(6), Erk-mediated phosphorylation speci fically inhibits the nuclear accumulation of Smad1. Thus, Smad1 receiv es opposing regulatory inputs through RTKs and RS/TKs, and it is this balance that determines the level of Smad1 activity in the nucleus, an d so possibly the role of Smad1 in the control of cell fate.