TGF-beta and related members of the cytokines play a central role in growth and development in higher organisms. In C. elegans three important aspects of development have been described that are mediated through TGF-beta signaling pathway. These include the dauer formation (Estevez et al., 1993), control of body size, and male tail morphogensis (Morita et al., 1999; Suzuki et al, 1999), and the axonal guidance (Clovita et al., 1998). We have found that the TGF-beta signaling also mediates endocytosis in the intestinal epithelium of C. elegans . Mutants in TGF-beta receptor family of Ser/Thr kinases,
daf-1 and
daf-4 (Georgi et al., 1990; Estevez et al., 1993), show abnormal endocytosis. Activation of TGF-beta receptor induced endocytosis of albumin in intestine is dependent on the endocytic machinery that includes, dynamin, clathrin heavy chain,
rab-5,
rab-11, and alpha and beta adaptin. We have extended these findings to show the role of TGF-beta receptors in albumin endocytosis in monolayers of endothelial cells by inhibiting endocytosis with receptor antibodies and its augmentation in cells transfected with cDNA encoding the receptor (Attisano et al., 1993). TGF-beta receptor mediated albumin endocytosis specifically activates Smad2 phosphorylation, Smad4 translocation, MAPK
p38 phosphorylation, and promotes cell growth and is anti-apoptotic. We propose a model that suggests that activation of endocytosis promotes cell growth and is anti-apoptotic. Thus, interaction of albumin with TGF-beta receptors is critical in regulating its endocytosis and the downstream activation of the TGF-beta signaling pathway. We thank A. Malik for enthusiastic support, and lively discussions, D. Riddle, S. Uddin, L. Jacobson, J. Massague, P. ten-Dijke, K. Miyazono, A. Shajahan, P. Okemma, T. Orenic, T. Stiernagle, and the CGC for strains, reagents and invaluable suggestions.