Regulation of activin/nodal signaling by Rap2-directed receptor trafficking.
We show that Rap2, a member of the Ras GTPase family, positively regulates Activin/Nodal signaling activity by controlling the trafficking of its receptors. In the absence of ligand activation, Rap2 directs internalized Activin/Nodal receptors into a recycling pathway, thereby preventing their degradation and maintaining their levels on the cell surface. Upon ligand activation, Rap2 no longer promotes receptor recycling but delays its turnover. In both cases, Rap2 contributes to upregulation of signaling activity by antagonizing Smad7. In addition, we found that the efficiency of Activin/Nodal receptor recycling is different between dorsal and ventral halves of Xenopus early embryo, which results from the asymmetric expression of Rap2 and Smad7. Consequently, they regulate cell responsiveness to ligands and the spatiotemporally dynamic activation of Smad2 along the dorsoventral axis of the embryo. Therefore, these findings suggest a molecular basis for the regulation of signaling activity and embryonic patterning by Activin/Nodal receptor trafficking.
Choi
Sun-Cheol
SC
Division of Molecular and Life Sciences, Pohang University of Science and Technology, San31, Hyoja-dong, Pohang, Kyungbuk 790-784, Korea.
Kim
Gun-Hwa
GH
Lee
Seung Joon
SJ
Park
Eunjoo
E
Yeo
Chang-Yeol
CY
Han
Jin-Kwan
JK
D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D028341:Activins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D019521:Body Patterning; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000502:physiology; D004705:Endocytosis; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008845:Microinjections; D055457:Nodal Protein; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology / Q000502:physiology; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020668:rap GTP-Binding Proteins / Q000378:metabolism*
D008024:Ligands; C526007:NODAL protein, human; D055457:Nodal Protein; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D051899:Smad2 Protein; C497785:Smad2 protein, Xenopus; D051906:Smad7 Protein; C497809:Smad7 protein, Xenopus; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; D028341:Activins; D008156:Luciferases; D030201:Activin Receptors, Type I; C530501:RAP2A protein, Xenopus; D020668:rap GTP-Binding Proteins