Tài liệu Báo cáo khoa học: What MAN1 does to the Smads TGFb/BMP signaling and the nuclear envelope

MINIREVIEW

What MAN1 does to the Smads

TGFb/BMP signaling and the nuclear envelope

Luiza Bengtsson

Institute for Chemistry and Biochemistry, Free University Berlin, Germany

Introduction

Our knowledge about the nuclear membrane has

advanced dramatically in the recent years. We now

know that protein residents of the nuclear membrane

regulate processes as diverse as DNA replication and

transcription, control of the shape and stability of the

nucleus, cell cycle progression, chromatin organiza￾tion, cell development and differentiation, nuclear

anchoring and migration, and apoptosis (reviewed in

[1,2]). Mutations in several of the integral membrane

proteins of the inner nuclear membrane (emerin,

MAN1, lamin B receptor) and their common binding

partners (lamins) cause distinct diseases, the molecular

mechanisms of which are not yet understood [1,3,4].

One of the current hypotheses suggests that the

diseases result from altered gene expression in affec￾ted tissues and that integral membrane proteins of

the inner nuclear membrane (INM) regulate gene

expression either directly, or as components of tran￾scription regulating protein complexes [3,5,6]. Indeed,

both emerin and MAN1 bind the transcriptional

repressors germ cell-less (GCL) and Bcl-2-associated

transcription factor (Btf) [7,8]. In addition, loss of

emerin leads to up-regulation of expression of 28

genes, which can be rescued by reintroducing emerin

[9]. LAP2b, another INM protein, can repress trans￾cription by recruiting histone deacetylase [10], or

Keywords

BMP; laminopathy; MAN1; nuclear

envelope; phosphatase; signal transduction;

Smad; TGFb

Correspondence

L. Bengtsson, Institute for Chemistry and

Biochemistry, Free University Berlin,

Thielallee 63 14195 Berlin, Germany

Tel: +49 30 838 54789

E-mail: [email protected]

Previous address

Department of Cell Biology, Johns Hopkins

University School of Medicine, 725 N. Wolfe

St, Baltimore, MD 21205, USA

(Received 8 March 2006, accepted 8 Janu￾ary 2007)

doi:10.1111/j.1742-4658.2007.05696.x

The inner nuclear membrane protein MAN1 has been identified as an

important factor in transforming growth factor b ⁄ bone morphogenic pro￾tein (TGFb ⁄BMP) signaling. Loss of MAN1 results in three autosomal

dominant diseases in humans; all three characterized by increased bone

density. Xenopus embryos lacking MAN1 develop severe morphological

defects. Both in humans and in Xenopus embryos the defects originate from

deregulation of TGFb ⁄BMP signaling. Several independent studies have

shown that MAN1 is antagonizing TGFb ⁄BMP signaling through binding

to regulatory Smads. Here, recent progress in understanding MAN1 func￾tions is summarized and a model for MAN1-dependent regulation of

TGFb ⁄BMP signaling is proposed.

Abbreviations

BAF, barrier-to-autointegration factor; BMP, bone morphogenic protein; Btf, Bcl-2-associated transcription factor; GCL, germ cell-less;

INM, inner nuclear membrane; LAP, lamina associated polypeptide; MH-domain, Mad homology domain; pRb, retinoblastoma protein;

PP, protein phosphatase; RR-motif, RNA recognition motif; R-Smads, regulatory Smads; SANE, Smad1 antagonistic effector; TGFb,

transforming growth factor b; UHM, U2AF homology motif; WH, winged-helix.

1374 FEBS Journal 274 (2007) 1374–1382 ª 2007 The Author Journal compilation ª 2007 FEBS