Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFβ signaling complexes in the cytoplasm and nucleus

Lan Xu; Yibin Kang; Seda Çöl; Joan Massagué

doi:10.1016/S1097-2765(02)00586-5

Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFβ signaling complexes in the cytoplasm and nucleus

Lan Xu, Yibin Kang, Seda Çöl, Joan Massagué

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

217 Scopus citations

Abstract

The transcription factor Smad2 is released from cytoplasmic retention by TGFβ receptor-mediated phosphorylation, accumulating in the nucleus where it associates with cofactors to regulate transcription. We uncovered direct interactions of Smad2 with the nucleoporins CAN/Nup214 and Nup153. These interactions mediate constitutive nucleocytoplasmic shuttling of Smad2. CAN/Nup214 and Nup153 compete with the cytoplasmic retention factor SARA and the nuclear Smad2 partner FAST-1 for binding to a hydrophobic corridor on the MH2 surface of Smad2. TGFβ receptor-mediated phosphorylation stimulates nuclear accumulation of Smad2 by modifying its affinity for SARA and Smad4 but not for CAN/Nup214 or Nup153. Thus, by directly contacting the nuclear pore complex, Smad2 undergoes constant shuttling, providing a dynamic pool that is competitively drawn by cytoplasmic and nuclear signal transduction partners.

Original language	English (US)
Pages (from-to)	271-282
Number of pages	12
Journal	Molecular Cell
Volume	10
Issue number	2
DOIs	https://doi.org/10.1016/S1097-2765(02)00586-5
State	Published - Aug 2002
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1016/S1097-2765(02)00586-5

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title = "Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFβ signaling complexes in the cytoplasm and nucleus",

abstract = "The transcription factor Smad2 is released from cytoplasmic retention by TGFβ receptor-mediated phosphorylation, accumulating in the nucleus where it associates with cofactors to regulate transcription. We uncovered direct interactions of Smad2 with the nucleoporins CAN/Nup214 and Nup153. These interactions mediate constitutive nucleocytoplasmic shuttling of Smad2. CAN/Nup214 and Nup153 compete with the cytoplasmic retention factor SARA and the nuclear Smad2 partner FAST-1 for binding to a hydrophobic corridor on the MH2 surface of Smad2. TGFβ receptor-mediated phosphorylation stimulates nuclear accumulation of Smad2 by modifying its affinity for SARA and Smad4 but not for CAN/Nup214 or Nup153. Thus, by directly contacting the nuclear pore complex, Smad2 undergoes constant shuttling, providing a dynamic pool that is competitively drawn by cytoplasmic and nuclear signal transduction partners.",

author = "Lan Xu and Yibin Kang and Seda {\c C}{\"o}l and Joan Massagu{\'e}",

note = "Funding Information: We are particularly grateful to Drs. B.R. Cullen and Y. Shi for valuable plasmids and recombinant proteins. We also thank Drs. G. Grosveld, J. Wrana, D. Gorlich, B. Paschal, S. Wente, B. Fontura, G. Blobel, and F. Stutz for plasmids and cell line used in this study. We thank Dr. Y. Shi for help with illustration of the Smad2/SARA crystal structure. This work was supported by NIH grant CA34610. L.X. and Y.K are supported by a Damon Runyon Walter Winchell fellowship (DRG-1540) from the Cancer Research Fund and a fellowship from the Irvington Institute for Immunological Research, respectively. J.M. is an investigator with the Howard Hughes Medical Institute.",

year = "2002",

month = aug,

doi = "10.1016/S1097-2765(02)00586-5",

language = "English (US)",

volume = "10",

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journal = "Molecular Cell",

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AU - Xu, Lan

AU - Kang, Yibin

AU - Çöl, Seda

AU - Massagué, Joan

N1 - Funding Information: We are particularly grateful to Drs. B.R. Cullen and Y. Shi for valuable plasmids and recombinant proteins. We also thank Drs. G. Grosveld, J. Wrana, D. Gorlich, B. Paschal, S. Wente, B. Fontura, G. Blobel, and F. Stutz for plasmids and cell line used in this study. We thank Dr. Y. Shi for help with illustration of the Smad2/SARA crystal structure. This work was supported by NIH grant CA34610. L.X. and Y.K are supported by a Damon Runyon Walter Winchell fellowship (DRG-1540) from the Cancer Research Fund and a fellowship from the Irvington Institute for Immunological Research, respectively. J.M. is an investigator with the Howard Hughes Medical Institute.

PY - 2002/8

Y1 - 2002/8

N2 - The transcription factor Smad2 is released from cytoplasmic retention by TGFβ receptor-mediated phosphorylation, accumulating in the nucleus where it associates with cofactors to regulate transcription. We uncovered direct interactions of Smad2 with the nucleoporins CAN/Nup214 and Nup153. These interactions mediate constitutive nucleocytoplasmic shuttling of Smad2. CAN/Nup214 and Nup153 compete with the cytoplasmic retention factor SARA and the nuclear Smad2 partner FAST-1 for binding to a hydrophobic corridor on the MH2 surface of Smad2. TGFβ receptor-mediated phosphorylation stimulates nuclear accumulation of Smad2 by modifying its affinity for SARA and Smad4 but not for CAN/Nup214 or Nup153. Thus, by directly contacting the nuclear pore complex, Smad2 undergoes constant shuttling, providing a dynamic pool that is competitively drawn by cytoplasmic and nuclear signal transduction partners.

AB - The transcription factor Smad2 is released from cytoplasmic retention by TGFβ receptor-mediated phosphorylation, accumulating in the nucleus where it associates with cofactors to regulate transcription. We uncovered direct interactions of Smad2 with the nucleoporins CAN/Nup214 and Nup153. These interactions mediate constitutive nucleocytoplasmic shuttling of Smad2. CAN/Nup214 and Nup153 compete with the cytoplasmic retention factor SARA and the nuclear Smad2 partner FAST-1 for binding to a hydrophobic corridor on the MH2 surface of Smad2. TGFβ receptor-mediated phosphorylation stimulates nuclear accumulation of Smad2 by modifying its affinity for SARA and Smad4 but not for CAN/Nup214 or Nup153. Thus, by directly contacting the nuclear pore complex, Smad2 undergoes constant shuttling, providing a dynamic pool that is competitively drawn by cytoplasmic and nuclear signal transduction partners.

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Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFβ signaling complexes in the cytoplasm and nucleus

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