Receptor internalization-independent activation of Smad2 in activin signaling.
Activin, a member of the TGFbeta 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 TGFbeta receptors endocytose to early endosomes, where they phosphorylate Smads. However, whether TGFbeta 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.
Zhou
Yunli
Y
Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Scolavino
Staci
S
Funderburk
Sarah F
SF
Ficociello
Laura F
LF
Zhang
Xun
X
Klibanski
Anne
A
D028341:Activins / Q000235:genetics / Q000378:metabolism*; D000409:Alanine / Q000235:genetics; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017354:Point Mutation; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014364:Tryptophan / Q000235:genetics
D004268:DNA-Binding Proteins; D011506:Proteins; D051899:Smad2 Protein; D015534:Trans-Activators; D028341:Activins; D014364:Tryptophan; D000409:Alanine; D011188:Potassium