Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal.
BMP receptors determine the intensity of BMP signals via Smad1 C-terminal phosphorylations. Here we show that a finely controlled cell biological pathway terminates this activity. The duration of the activated pSmad1(Cter) signal was regulated by sequential Smad1 linker region phosphorylations at conserved MAPK and GSK3 sites required for its polyubiquitinylation and transport to the centrosome. Proteasomal degradation of activated Smad1 and total polyubiquitinated proteins took place in the centrosome. Inhibitors of the Erk, p38, and JNK MAPKs, as well as GSK3 inhibitors, prolonged the duration of a pulse of BMP7. Wnt signaling decreased pSmad1(GSK3) antigen levels and redistributed it from the centrosome to cytoplasmic LRP6 signalosomes. In Xenopus embryos, it was found that Wnts induce epidermis and that this required an active BMP-Smad pathway. Epistatic experiments suggested that the dorsoventral (BMP) and anteroposterior (Wnt/GSK3) patterning gradients are integrated at the level of Smad1 phosphorylations during embryonic pattern formation.
Howard Hughes Medical Institute and Department of Biological Chemistry, University of California, Los Angeles, CA 90095-1662, USA.
Luis C
LC
Fuentealba
Edward
E
Eivers
Atsushi
A
Ikeda
Cecilia
C
Hurtado
Hiroki
H
Kuroda
Edgar M
EM
Pera
Edward M
EM
De Robertis
D000595:Amino Acid Sequence; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000502:physiology; D019556:COS Cells; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism; D002522:Chlorocebus aethiops; D004625:Embryo, Nonmammalian; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology*; D051898:Smad1 Protein / Q000378:metabolism* / Q000502:physiology; D013997:Time Factors; D054875:Ubiquitination / Q000502:physiology; D051153:Wnt Proteins / Q000502:physiology*; D014981:Xenopus / Q000196:embryology
D019485:Bone Morphogenetic Proteins; D051898:Smad1 Protein; D051153:Wnt Proteins; D038362:Glycogen Synthase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases