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Papers In Press, published online ahead of print January 12, 2005
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720-3206
Corresponding Author: kluo{at}berkeley.edu
Smad proteins are critical intracellular mediators of the transforming growth factor-
J. Biol. Chem, 10.1074/jbc.M411234200
Submitted on October 1, 2004
Revised on January 12, 2005
Accepted on January 12, 2005
The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the TGF
superfamily of cytokines
, BMP 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 TGF, BMP2 and activin responsive promoters. This repression of TGF, BMP2 and activin signaling is dependent on the MAN1-Smad interaction since a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-Smad regulator and defines a previously unrecognized regulatory step at the nuclear periphery.
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