LIMD1 (LIM domains containing 1)

Other alias
HGNC (Hugo)	LIMD1
LocusID (NCBI)	8994
Atlas_Id	41158
Location	3p21.31  [Link to chromosome band 3p21]
Location_base_pair	Starts at 45594831 and ends at 45681263 bp from pter ( according to hg19-Feb_2009)  [Mapping LIMD1.png]
Local_order	TMEM158, LARS2, LIMD1, SACM1L, SLC6A20, LZTFL1.

	The eight exons of the LIMD1 gene are denoted by open rectangles; the protein coding regions of the exons are coloured in blue. Exons 2 to 8 encode three LIM domains in tandem. Exon 1 encodes the N-terminal pre-LIM region. Regions important for transcriptional regulation upstream of the start codon (ATG, +1) are denoted by black rectangles. Experimental evidence suggests that a negative regulatory element (-ve RE) occurs in the region between -2039 and -1539. The CpG island between -1299 and -439 contains a putative TATA box at -439 (yellow circle) and a 21-bp core promoter region at -727 (green circle).
Description	The gene encompasses 86432 bp and lies in the plus strand, starting at 45636323 and ending at 45722754 bp from pter, within C3CER1 (chromosome 3 common eliminated region 1) at chromosome 3p21.3, a region frequently deleted in solid tumours. The 5'-promoter region includes a negative regulatory element and a CpG island that contains a putative TATA box and an experimentally validated core basal promoter region of 21 bp (Sharp et al., 2008). The core promoter region contains four CpG methylation sites (Sharp et al., 2008).
Transcription	The transcript (NCBI ID: NM_014240.2) of 6284 bp comprises eight exons, the first of which encodes the N-terminal pre-LIM region. Exons 2 to 8 encode three LIM domains in tandem. The size of the open reading frame is 5129 bp.
Pseudogene	None known.

	LIMD1 can be split primarily into the N-terminal pre-LIM region (residues 1 to 471) and the C-terminal triple LIM domains (residues 472 to 676). The pre-LIM region contains a proline/serine-rich region (residues 69 to 471), a LEM-like domain (residues 18 to 68), a nuclear export signal (NES, residues 54 to 134) and the binding site for pRB (residues 404 to 442). The three LIM domains are an inherent nuclear localisation signal (NLS, residues 472 to 676).
Description	LIMD1 (676 amino acids, 72 kDa, NCBI ID: NP_055055.1) belongs to the Ajuba LIM protein subgroup of the Ajuba/Zyxin protein family. This six-member family (see Homology) is characterised by a varied proline-rich pre-LIM region at the N-terminus followed by three homologous LIM domains arranged in tandem at the C-terminus. LIM domains (InterPro ID: IPR001781) coordinate two zinc ions in a tandem zinc-finger topology and mediate protein-protein interactions (Kadrmas and Beckerle, 2004). The three LIM domains of LIMD1 are an inherent nuclear localisation signal (NLS) (Sharp et al., 2004). The pre-LIM region includes the pRB binding region and a nuclear export signal (NES) partially overlapping the N-terminal LEM-like domain (Sharp et al., 2004).
Expression	LIMD1 is ubiquitously expressed, but at a lower level in the brain and testis (Kiss et al., 1999).
Localisation	LIMD1 shuttles between the cytoplasm and nucleus, but is not found in the nucleoli (Sharp et al., 2004). In the cytoplasm, LIMD1 colocalises with focal adhesions (Huggins and Andrulis, 2008; Petit et al., 2005), adherens junctions (Das Thakur et al., 2010) and mRNA processing bodies (P-bodies) (James et al., 2010).
Function	LIMD1 is involved in a range of cellular functions (listed below). A common theme is that LIMD1 acts as a protein-protein scaffold or mediator to facilitate signalling between cytoplasmic components and the nucleus. Functional redundancy between LIMD1 and the other Ajuba LIM proteins has also been proposed in a variety of cases (Das Thakur et al., 2010; Feng and Longmore, 2005; James et al., 2010; Langer et al., 2008). - LIMD1 inhibits E2F-mediated transcription and thus cell proliferation via interaction with pRB and also via a pRB-independent mechanism that has yet to be clarified (Sharp et al., 2004). - LIMD1 stimulates stress osteoclastogenesis (Feng et al., 2007) and regulates osteoblast differentiation and function (Luderer et al., 2008). LIMD1 can act as both a positive regulator of osteoclast and osteoblast development, by linking the p62/sequestosome protein and TRAF6 to form a p62/TRAF6/a-PKC complex which can activate NF-kB and AP-1 (Feng and Longmore, 2005; Feng et al., 2007), and a negative regulator of osteoblast differentiation, by repressing canonical Wnt/beta-catenin signalling in osteoblasts (Luderer et al., 2008). - LIMD1 facilitates miRNA-mediated silencing by (i) binding to eIF4E to prevent recruitment of 4EBP1 and eIF4G to the mRNA 5' m(7)GTP cap, and (ii) creating an inhibitory closed-loop complex by acting as a scaffold to link eIF4E at the 5' cap to Ago1/Ago2 in the miRISC complex bound at the 3' UTR of mRNA (James et al., 2010). - LIMD1 interacts with LATS/Warts and WW45/Sav to inhibit Hippo (Hpo) signalling pathway-mediated phosphorylation and nuclear-targeting of YAP/Yki (Das Thakur et al., 2010). Implication of the Hpo pathway in cell contact growth inhibition, and the observation that in confluent cells with no further proliferation, Ajuba LIM proteins gather at adherens junctions whilst YAP is phosphorylated and returned to the cytosol has led Das Thakur et al. (2010) to propose that Ajuba LIM proteins "release" LATS/Warts upon localisation at adherens junctions, leading to growth inhibition. - In the nucleus, LIMD1 interacts with the SNAG domain of Snail/Slug transcriptional repressors and acts as a co-repressor of E-cadherin and other Snail-regulated genes to affect neural crest development and possibly epithelial-mesenchymal transitions (Langer et al., 2008). - Huggins and Andrulis (2008) suggested that LIMD1 may play a part in cell anchoring as a component of focal adhesions and in the cell cycle (especially during mitosis), based on the respective observations that LIMD1 colocalises with vinculin at focal adhesions and that phosphorylation of LIMD1 occurs during mitosis in HeLa cells.
Homology	The phylogenetic tree below shows the evolutionary distance (as inferred from amino acid sequence) between LIMD1 and the five other members of the Ajuba/Zyxin protein family (James et al., 2010). LIMD1 is most closely related to the other Ajuba LIM proteins, Ajuba and WTIP (respectively 41% and 39% identity overall and 64% and 72% identity in the LIM domains). In contrast, LIMD1 shares only 32%, 33% and 34% identity overall and 43%, 46% and 41% identity in the LIM domains with the Zyxin LIM proteins, Zyxin, LPP and TRIP6 respectively. The orthologue of LIMD1 in mus musculus shares 77% identity overall and 96% identity in the LIM domains with human LIMD1.

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