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PMID:15647271

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Citation

Pan, D, Estévez-Salmerón, LD, Stroschein, SL, Zhu, X, He, J, Zhou, S and Luo, K (2005) The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines. J. Biol. Chem. 280:15992-6001

Abstract

Smad proteins are critical intracellular mediators of the transforming growth factor-beta, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-Smads are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-Smads then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with various transcription factors to regulate the expression of downstream genes. Interaction of Smad proteins with cellular partners in the cytoplasm and nucleus is a critical mechanism by which the activities and expression of the Smad proteins are modulated. Here we report a novel step of regulation of the R-Smad function at the inner nuclear membrane through a physical interaction between the integral inner nuclear membrane protein MAN1 and R-Smads. MAN1, through the RNA recognition motif, associates with R-Smads but not Smad4 at the inner nuclear membrane in a ligand-independent manner. Overexpression of MAN1 results in inhibition of R-Smad phosphorylation, heterodimerization with Smad4 and nuclear translocation, and repression of transcriptional activation of the TGFbeta, BMP2, and activin-responsive promoters. This repression of TGFbeta, BMP2, and activin signaling is dependent on the MAN1-Smad interaction because a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-Smad regulators and defines a previously unrecognized regulatory step at the nuclear periphery.

Links

PubMed Online version:10.1074/jbc.M411234200

Keywords

Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins/metabolism; DNA-Binding Proteins/metabolism; Humans; Membrane Proteins/genetics; Membrane Proteins/metabolism; Nuclear Envelope/metabolism; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Phosphorylation; Promoter Regions, Genetic; Signal Transduction; Smad Proteins; Trans-Activators/metabolism; Transforming Growth Factor beta/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SMAD3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y2U8

F

Seeded From UniProt

complete

HUMAN:SMAD3

located_in

GO:0005637: nuclear inner membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMAD2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y2U8

F

Seeded From UniProt

complete

HUMAN:SMAD1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y2U8

F

Seeded From UniProt

complete

HUMAN:SMAD1

located_in

GO:0005637: nuclear inner membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMAD5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9Y2U8

F

Seeded From UniProt

complete

HUMAN:MAN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P84022

F

Seeded From UniProt

complete

HUMAN:MAN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15796

F

Seeded From UniProt

complete

HUMAN:MAN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q99717

F

Seeded From UniProt

complete

HUMAN:MAN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15797

F

Seeded From UniProt

complete

HUMAN:MAN1

involved_in

GO:0030514: negative regulation of BMP signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MAN1

involved_in

GO:0030512: negative regulation of transforming growth factor beta receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MAN1

located_in

GO:0005637: nuclear inner membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MAN1

involved_in

GO:0032926: negative regulation of activin receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMAD1

part_of

GO:0005637: nuclear inner membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMAD3

part_of

GO:0005637: nuclear inner membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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