SANE, a Novel LEM Domain Protein, Regulates Bone Morphogenetic Protein Signaling through Interaction with Smad1

Raju, G. Praveen; Dimova, Neviana; Klein, Peter S.; Huang, Hui‐Chuan

doi:10.1074/jbc.m210505200

Cited by 87 publications

(80 citation statements)

References 68 publications

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“…LEM-D proteins interact with transcriptional repressors, such as germ cell-less and Bcl-2-associated transcription factor (Haraguchi et al 2004;Mansharamani and Wilson 2005). In addition, interactions with the downstream transcriptional effectors of multiple signal transduction pathways have been observed, such as Smads [receptor-regulated (R)-Smads], retinoblastoma protein, and b-catenin (Markiewicz et al 2002(Markiewicz et al , 2006Osada et al 2003;Raju et al 2003;Lin et al 2005;Pan et al 2005;Jiang et al 2008). These latter observations suggest that LEM-D proteins have a role in the regulation of gene expression.…”

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confidence: 81%

“…Analysis of LEMD3 mutant alleles suggests that disease phenotypes result from haploinsufficiency, as these alleles produce truncated proteins that lack the carboxyl-terminal protein recognition domain called the U2AF homology motif (UHM), a domain related to an RNA recognition motif (RRM) (Kielkopf et al 2004). Loss of the UHM/ RRM is proposed to increase TGF-b/BMP signaling due to the failure of MAN1 to interact with R-Smads (Osada et al 2003;Raju et al 2003;Lin et al 2005;Pan et al 2005). Disease phenotypes caused by LMNA mutations overlap with those caused by the loss of MAN1 (Lee and Wilson 2004;Arimura et al 2005), implying that the loss of one nuclear lamina component may alter the function of other proteins in the network.…”

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confidence: 99%

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Tissue-Specific Defects Are Caused by Loss of the Drosophila MAN1 LEM Domain Protein

Pinto¹,

Wilmington

Hornick

et al. 2008

Genetics

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The nuclear lamina represents a protein network required for nuclear structure and function. One family of lamina proteins is defined by an $40-aa LAP2, Emerin, and MAN1 (LEM) domain (LEM-D) that binds the nonspecific DNA-binding protein, barrier-to-autointegration factor (BAF). Through interactions with BAF, LEM-D proteins serve as a bridge between chromosomes and the nuclear envelope. Mutations in genes encoding LEM-D proteins cause human laminopathies that are associated with tissue-restricted pathologies. Drosophila has five genes that encode proteins with LEM homology. Using yeast two-hybrid analyses, we demonstrate that four encode proteins that bind Drosophila (d)BAF. In addition to dBAF, dMAN1 associates with lamins, the LEM-D protein Bocksbeutel, and the receptor-regulated Smads, demonstrating parallel protein interactions with vertebrate homologs. P-element mobilization was used to generate null dMAN1 alleles. These mutants showed decreased viability, with surviving adults displaying male sterility, decreased female fertility, wing patterning and positioning defects, flightlessness, and locomotion difficulties that became more severe with age. Increased phospho-Smad staining in dMAN1 mutant wing discs is consistent with a role in transforming growth factor (TGF)-b/bone morphogenic protein (BMP) signaling. The tissuespecific, age-enhanced dMAN1 mutant phenotypes are reminiscent of human laminopathies, suggesting that studies in Drosophila will provide insights into lamina dysfunction associated with disease.

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confidence: 81%

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confidence: 99%

Tissue-Specific Defects Are Caused by Loss of the Drosophila MAN1 LEM Domain Protein

Pinto¹,

Wilmington

Hornick

et al. 2008

Genetics

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“…Roughly three decades ago, lamins became the first NE proteins characterized -in large part because they are the most abundant proteins in isolated NEs [21,22]. Subsequently a number of NE transmembrane proteins (Table 1) proteins: SANE is a LEM domain-containing protein that functions in the cytoplasm and does not appear in a nuclear fraction [48], and there are LEM domain-containing splice variants of LAP2 without a transmembrane sequence that are concentrated in the nuclear interior [49]. This emphasizes the importance of combining genomic and cell biological approaches to clarify protein localization and function.…”

Section: Roads To the Nuclear Envelope Proteomementioning

confidence: 99%

The nuclear membrane proteome: extending the envelope

Schirmer

Gerace

2005

Trends in Biochemical Sciences

128

109

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The marriage of proteomics with cell biology has produced extensive inventories of the proteins that inhabit several subcellular organelles. Recent proteomic analysis has identified a large number of new putative transmembrane proteins in the nuclear envelope, and transcriptome profiling suggests that the nuclear membrane proteome exhibits some significant variations among different tissues. Cell type-specific differences in the composition of protein subcomplexes of the nuclear envelope, particularly those containing the disease-associated protein lamin A, could yield distinctive functions and so explain the tissue-specificity of a diverse group of nuclear envelope-linked disorders in humans. Considered together, these recent results suggest an unexpected functional complexity at the nuclear envelope.3 An introduction to the nuclear envelopeThe past few years have seen an explosion in the number of identified nuclear envelope (NE) proteins as well as in the number of their associated diseases. The NE (Figure 1), which is continuous with the more peripheral ER, contains an outer (ONM) and inner nuclear membrane (INM) that are joined at the nuclear pore membrane, giving rise to three different subdomains within nuclear membranes. The ONM is functionally similar to the more peripheral ER, but also is thought to contain some distinct resident proteins. The INM contains a large group of distinctive transmembrane proteins and is lined by a polymer of intermediate filament proteins called lamins. As many as four major lamin subtypes (lamin A, C, B1, and B2) are expressed in mammalian cells in a developmentally-regulated manner. Most lamin subtypes can be modified with lipid moieties that facilitate their targeting to the NE, and a fraction of some lamins occurs in the nucleoplasm as well as at the INM (reviewed in [1]). The lamin polymer and interacting proteins at the INM collectively comprise the nuclear lamina. The nuclear pore membrane is closely associated with nuclear pore complexes (NPCs), the main macromolecular transport channels across the NE. The transport functions and proteome of the NPC have been extensively characterized [2,3], and will not be further considered here. It is generally agreed that the lamina has a role in nuclear morphology and stability [4][5][6], and support for a wide and ever-increasing array of additional functions has emerged from recent studies. Lamins and lamina-associated membrane proteins have been linked to activities as diverse as transcription [7][8][9][10], DNA replication [11,12], nuclear anchoring/ migration within the cell [13], and signaling cascades [14]. To what extent these are direct or indirect effects of lamina proteins remains to be elucidated. 4Consistent with the notion that the nuclear lamina is involved in a diverse range of basic cellular functions, at least fifteen inherited diseases and syndromes have been linked to lamins A/C and certain associated NE transmembrane proteins.These include muscular dystrophies, lipodystrophies, neuropathy, cardiomyo...

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“…Raju et al [2003] performed a yeast two-hybrid screen using Xenopus Smad1 as bait and identified the frog MAN1 orthologue, which they called SANE for Smad1 antagonistic effector. The carboxyl-terminal domain of this Xenopus protein bound to the MH2 domain of Smad1.…”

Section: Man1 Regulates Smad Signalingmentioning

confidence: 99%

Inner nuclear membrane and signal transduction

Worman

2005

J of Cellular Biochemistry

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Recent research has shown that the inner nuclear membrane is a site for regulation of signal transduction from the plasma membrane to the nucleus. This has coincided with discoveries showing that mutations in extrinsic and intrinsic inner nuclear membrane proteins cause a variety of inherited diseases. In most instances, the mechanisms by which mutations in inner nuclear membrane proteins cause disease are not understood. In at least one case, however, an alteration in signal transduction appears to underlie disease pathogenesis.

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SANE, a Novel LEM Domain Protein, Regulates Bone Morphogenetic Protein Signaling through Interaction with Smad1

Cited by 87 publications

References 68 publications

Tissue-Specific Defects Are Caused by Loss of the Drosophila MAN1 LEM Domain Protein

Tissue-Specific Defects Are Caused by Loss of the Drosophila MAN1 LEM Domain Protein

The nuclear membrane proteome: extending the envelope

Inner nuclear membrane and signal transduction

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