NEDD9

2L81473918003ENSG00000111859ENSMUSG00000021365Q14511O35177NM_001142393NM_001271033NM_006403NM_182966NM_001111324NM_017464NP_001135865NP_001257962NP_006394NP_892011NP_001104794NP_059492Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the NEDD9 gene. NEDD-9 is also known as enhancer of filamentation 1 (EF1), CRK-associated substrate-related protein (CAS-L), and Cas scaffolding protein family member 2 (CASS2). An important paralog of this gene is BCAR1. Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the NEDD9 gene. NEDD-9 is also known as enhancer of filamentation 1 (EF1), CRK-associated substrate-related protein (CAS-L), and Cas scaffolding protein family member 2 (CASS2). An important paralog of this gene is BCAR1. In 1992, Kumar, et al., first described a sequence tag corresponding to the NEDD9 3′ untranslated region based on the cloning of a group of genes predominantly expressed in the brain of embryonic, but not adult mice, a group of genes designated neural precursor cell expressed, developmentally down-regulated. In 1996, two groups independently described the complete sequence of the NEDD9 gene, and provided initial functional analysis of NEDD9 protein. Law et al. overexpressed a human cDNA library in S. cerevisiae, and screened for genes that simultaneously affected cell cycle and cell polarity controls, inducing a filamentous yeast budding phenotype, and thus identified the HEF1 protein (Human Enhancer of Filamentation 1). This study identified HEF1/NEDD9 as an interactive partner for focal adhesion kinase (FAK), connecting it to integrin signaling. Separately, Minegishi et al. cloned the gene encoding a protein hyperphosphorylated following ligation of β1-integrins in T cells and hypothesized to play a role in the process of T cell costimulation, designating this gene Cas-L (Crk-associated substrate-related protein, Lymphocyte type). The genomic coordinates of the NEDD9 gene are 6:11,183,530-11,382,580 in the GRCh37 assembly, or 6:11,183,298-11,382,348 in the GRCh38 assembly. The gene is on the minus strand. The cytogenetic location is 6p25-p24, based on the nomenclature developed by the Human Genome Organization (HUGO) gene nomenclature committee (HGNC). NEDD9 is the HGNC approved symbol. Official IDs are 7733 (HGNC), 4739 (Entrez Gene), and ENSG00000111859 (Ensembl). CAS-L, CASL, HEF1, dJ49G10.2, dJ761I2.1, CAS2, CASS2 are alias symbols. The NEDD9 gene is conserved in Rhesus monkeys, dogs, cows, mice, rats, chickens, zebrafish, and frogs. In vertebrates, it is a member of a 4-gene family, with the other paralogous genes known as BCAR1 (p130Cas), EFS (Sin), and CASS4 (HEPL) The NEDD9 promoter has 2 transcriptional start sites. The transcript variants NM_006403.3 and NM_001142393.1 encode proteins that have distinct N-termini (MKYK and MWTR, respectively). In mouse, the two alternative first exons are MKYK and MWAR. Their function is not known. NM_001142393 initiates translation at an upstream location compared to NM_006403.3, but both transcripts have 7 exons. Shorter transcripts with missing exons or an alternative 3' terminal exon have been detected in various studies; however, their role in the cell is unclear. The 5' region of the NEDD9 promoter is regulated by all-trans retinoic acid (ATRA), and contains a retinoic acid response element (RARE) that is specifically bound by a retinoid X receptor (RXR)/retinoic acid receptor (RAR) heterodimer. NEDD9 is also induced by the environmental pollutant dioxin, based on regulation through the aryl hydrocarbon receptor (AhR). One study has found NEDD9 repressed by estrogen, based on binding of the SAFB1 co-repressor. NEDD9 is induced by Wnt signaling in colon cancer, based on binding to T-cell factor (TCF) factors in the promoter region. NEDD9 is induced by hypoxia and loss of VHL, based on binding of hypoxia-induced factor (HIF) transcription factors to the NEDD9 promoter. Prostaglandin E2 induces NEDD9 transcription. The Fox transcription factor Forkhead box C1 (FoxC1) and PAX5 transcription factor have been reported to induce NEDD9 transcription. TGF-beta induces NEDD9 transcription. Based on inspection of sequence, the NEDD9 promoter also has potential binding sites for a number of additional transcription factors, including STAT5A and NF-kappa B. In the 3'UTR of NEDD9 is a match to positions 2-8 of mature miR-145. NEDD9-binding regions in the miR-145 locus would allow the direct binding of the NEDD9 3'UTR to the genomic region of miR-145, and some studies suggests this miR regulates NEDD9 in glioblastoma prostate cancer, and renal cell carcinoma cells. A non-coding RNA, named B2, extending from 10 kb upstream of NEDD9 exon 1 to exon 4 has been described, but the functional role for this ncRNA is not yet clear. NEDD9 is highly expressed in the embryonal brain, and in numerous tissues in the embryo and adult organism. Elevated expression is associated with cancer, as discussed below. NEDD9 is a member of the CAS (Crk-associated substrate) protein family, which has 4 members in vertebrates. The other paralogous genes are known BCAR1 (p130Cas), EFS (Sin), and CASS4 (HEPL). There is no detectable NEDD9-related gene in bacteria, yeast, or C. elegans. A single family member exists in D. Melanogaster, termed DCas. In humans, NEDD9 is 834 amino acids long. NEDD9 is a noncatalytic scaffolding protein that contains docking sites for proteins involved in multiple signal transduction pathways, regulating magnitude and duration of cell signaling cascades The overall structure of NEDD9 is represented graphically in Figure 1.