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Receptor Internalization-Independent Activation of Smad2 in Activin Signaling

Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Massachusetts General Hospital, Neuroendocrine Unit, 55 Fruit Street, Bulfinch 457, Boston, Massachusetts 02114. E-mail: aklibanski{at}partners.org.

Activin, a member of the TGFß family of cytokines, signals through heteromeric transmembrane complexes composed of type I and type II Ser/Thr kinase receptors. Activated by type II receptors, the type I receptor phosphorylates, thereby activating its effectors Smad2 and Smad3. It has been shown that the ligand-bound TGFß receptors endocytose to early endosomes, where they phosphorylate Smads. However, whether TGFß and activin can signal without receptor internalization is still in question. We report that a mutation changing Trp₄₇₇ to Ala in the kinase domain rendered the type I activin receptor Alk4 unable to undergo ligand-dependent internalization. However, the resultant receptor, named Alk4W₄₇₇A, retained the ability to phosphorylate Smad2 and mediate activin-induced transcription activation. Also, a Trp₄₇₇ to Ala mutation abolished the endocytosis of Alk4T₂₀₆D, a constitutively active type I activin receptor. The action of the mutant Alk4T₂₀₆D became activin dependent. Finally, blocking endocytosis by depletion of intracellular potassium did not inhibit Smad2 phosphorylation by Alk4W₄₇₇A. Taken together, our data indicate that activin receptors can transduce activin signals without endocytosis and suggest the possibility that an endocytosis-independent activin signaling pathway exists, which may act as an alternative mechanism for signal transduction.

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