Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 22, Issue 13, Pages 4750-4759Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.22.13.4750-4759.2002
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Funding
- NCI NIH HHS [CA09441, T32 CA009441] Funding Source: Medline
- NIGMS NIH HHS [R01 GM054200, R01 GM055816, GM55816, GM54200, R37 GM055816] Funding Source: Medline
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Members of the transforming growth factor beta (TGF-beta) family of proteins signal through cell surface transmembrane serine/threonine protein kinases known as type I and type II receptors. The TGF-beta signal is extended through phosphorylation of receptor-associated Smad proteins by the type I receptor. Although numerous investigations have established the sequence of events in TGF-beta receptor (TGF-betaR) activation, none have examined the role of the endocytic pathway in initiation and/or maintenance of the signaling response. In this study we investigated whether TGF-betaR internalization modulates type I receptor activation, the formation of a functional receptor/Smad/SARA complex, Smad2/3 phosphorylation or nuclear translocation, and TGF-beta-dependent reporter gene activity. Our data provide evidence that, whereas type I receptor phosphorylation and association of SARA and Smad2 with the TGF-betaR complex take place independently of clathrin lattice formation, Smad2 or Smad3 activation and downstream signaling only occur after endocytic vesicle formation. Thus, TGF-betaR endocytosis is not simply a way to dampen the signaling response but instead is required to propagate signaling via the Smad pathway.
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