Integrating Patterning Signals: Wnt/GSK3 Regulates the Duration of the BMP/Smad1 Signal

Luis C. Fuentealba; Edward Eivers; Atsushi Ikeda; Cecilia Hurtado; Hiroki Kuroda; Edgar M. Pera; Edward M. De Robertis

doi:10.1016/j.cell.2007.09.027

Integrating Patterning Signals: Wnt/GSK3 Regulates the Duration of the BMP/Smad1 Signal

Luis C. Fuentealba, Edward Eivers, Atsushi Ikeda, Cecilia Hurtado, Hiroki Kuroda, Edgar M. Pera, Edward M. De Robertis

Research output: Contribution to journal › Article › peer-review

424 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	980-993
Number of pages	14
Journal	Cell
Volume	131
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2007.09.027
Publication status	Published - 2007 Nov 30
Externally published	Yes

Keywords

CELLBIO
DEVBIO
SIGNALING

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2007.09.027

Cite this

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title = "Integrating Patterning Signals: Wnt/GSK3 Regulates the Duration of the BMP/Smad1 Signal",

abstract = "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 pSmad1Cter 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 pSmad1GSK3 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.",

keywords = "CELLBIO, DEVBIO, SIGNALING",

author = "Fuentealba, {Luis C.} and Edward Eivers and Atsushi Ikeda and Cecilia Hurtado and Hiroki Kuroda and Pera, {Edgar M.} and {De Robertis}, {Edward M.}",

note = "Funding Information: We thank Drs. G. Thomsen, J. Massagu{\'e}, D. Bohmann, X. He, R. Moon, J. Slack, H. Clevers, P. ten Dijke, and C. Niehrs for reagents, Y. Sun for advice, and members of our laboratory for comments on the manuscript. This work was supported by the NIH (HD21502-21). C.H. was a recipient of a Heart & Stroke Foundation of Canada Fellowship. E.M. De R. is an investigator of the Howard Hughes Medical Institute. ",

year = "2007",

month = nov,

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doi = "10.1016/j.cell.2007.09.027",

language = "English",

volume = "131",

pages = "980--993",

journal = "Cell",

issn = "0092-8674",

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T1 - Integrating Patterning Signals

T2 - Wnt/GSK3 Regulates the Duration of the BMP/Smad1 Signal

AU - Fuentealba, Luis C.

AU - Eivers, Edward

AU - Ikeda, Atsushi

AU - Hurtado, Cecilia

AU - Kuroda, Hiroki

AU - Pera, Edgar M.

AU - De Robertis, Edward M.

N1 - Funding Information: We thank Drs. G. Thomsen, J. Massagué, D. Bohmann, X. He, R. Moon, J. Slack, H. Clevers, P. ten Dijke, and C. Niehrs for reagents, Y. Sun for advice, and members of our laboratory for comments on the manuscript. This work was supported by the NIH (HD21502-21). C.H. was a recipient of a Heart & Stroke Foundation of Canada Fellowship. E.M. De R. is an investigator of the Howard Hughes Medical Institute.

PY - 2007/11/30

Y1 - 2007/11/30

N2 - 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 pSmad1Cter 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 pSmad1GSK3 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.

AB - 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 pSmad1Cter 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 pSmad1GSK3 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.

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Integrating Patterning Signals: Wnt/GSK3 Regulates the Duration of the BMP/Smad1 Signal

Abstract

Keywords

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