Biology:NEDD9

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the NEDD9 gene.[1] 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.

Discovery

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.[2] 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).[3] 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).[4]

Gene

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.[5][6][7] NEDD9 is also induced by the environmental pollutant dioxin, based on regulation through the aryl hydrocarbon receptor (AhR).[8] One study has found NEDD9 repressed by estrogen, based on binding of the SAFB1 co-repressor.[9] NEDD9 is induced by Wnt signaling in colon cancer, based on binding to T-cell factor (TCF) factors in the promoter region.[10] NEDD9 is induced by hypoxia and loss of VHL, based on binding of hypoxia-induced factor (HIF) transcription factors to the NEDD9 promoter.[11][12][13] Prostaglandin E2 induces NEDD9 transcription.[14] The Fox transcription factor Forkhead box C1 (FoxC1)[15] and PAX5 transcription factor [16] have been reported to induce NEDD9 transcription. TGF-beta induces NEDD9 transcription.[17] 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[18] prostate cancer,[19] and renal cell carcinoma cells.[20] 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.[21] NEDD9 is highly expressed in the embryonal brain,[22] and in numerous tissues in the embryo and adult organism. Elevated expression is associated with cancer, as discussed below.

Protein family

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),[23] EFS (Sin),[24][25] and CASS4 (HEPL).[26] There is no detectable NEDD9-related gene in bacteria, yeast, or C. elegans. A single family member exists in D. Melanogaster, termed DCas.[27][28]

Structure

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 [29][30][31][32] The overall structure of NEDD9 is represented graphically in Figure 1.

NEDD9 structure

These domains include:

SH3 domain
This highly conserved N-terminal domain mediates NEDD9 binding to the polyproline motifs of a number of important interacting proteins, with some well-studied partners being FAK[3] and the related PYK2/RAFTK kinase,[33] C3G,[34] PTP-PEST,[35] PTP1B[36] and CIZ.[37]
Substrate domain (SD)
This unstructured region contains multiple YxxP motifs, which are phosphorylated by src family kinases (such as FYN, LCK and SRC) to create binding sites for proteins with SH2 domains, such as Crk.[4] Phosphorylation of these motifs can be activated by mechanical forces such as cytoskeletal stretch.[38] Other phosphorylation events in this region are imposed by the kinase Aurora-A, which phosphorylates residue S296, for processes related to cell cycle control.[39]
Serine rich (SR) region
The SR region likely folds into a 4-helix bundle, based on substantial predicted homology to BCAR1, for which the structure has been solved.[40]
Focal adhesion targeting (FAT) domain
The FAT-like C-terminal domain[41] is highly conserved in focal adhesion proteins, and sufficient for localizing focal adhesion kinase (FAK) to focal adhesions.[42] It forms a four-helix bundle structure and implicated in interaction with NSP proteins (novel SH2-containing protein family),[43][44] and other proteins such as the Id family of helix-loop-helix proteins.[45]

In terms of post-translational modifications, NEDD9 is subject to significant phosphorylation based on growth conditions. In most actively growing adherent cells, NEDD9 migrates as a doublet of 115 and 105 kDa. Serine/threonine hyper-phosphorylated p115 NEDD9 is more common in G2/M phase cells,[46] suggesting these modifications are associated with increased localization to centrosome and mitotic spindle. One study indicated the conversion of p115 into p105 is activated by cell detachment through cytoskeletal regulation of phosphatase PP2A,[47] although other work has found conflicting results.[48]

Synthesis and degradation

NEDD9 is present throughout cell cycle, but most abundant in G2/M phase cells.[46] NEDD9 is subject to both caspase cleavage and proteasomal degradation.[30][31] In conditions of cell detachment, and particularly in early stages of anoikis or apoptosis, NEDD9 is rapidly cleaved by caspases 3 and/or 7 at a DLVD site (residue 363), and at a DDYD site (residue 630) [49] to form N-terminal 55 KDa and C-terminal 28 KDa fragments forms. This cleavage is prevented by focal adhesion formation, which suggests NEDD9 as a sensor of altered adhesion states.[46][50] Overexpression of p28 in cells causes cellular rounding and detachment, and induces apoptosis,[50] probably because of a dominant-negative effect on survival-promoting signaling complexes at focal adhesions. Together this data suggests that production of different NEDD9 posttranslational modifications is regulated by cell de/attachment, which, in turn, allows regulation of NEDD9 turnover and participation in distinct cellular processes.

P115 is the primary target for proteasomal degradation of NEDD9.[47] Proteasomal degradation of NEDD9 is triggered by a number of stimuli, including induction of TGF-beta signaling.[51] An effector of the TGFbeta receptor, Smad3, may interact directly with APC subunit APC10 and thus recruit the APC complex. CDH1 subunit of the APC complex recognizes NEDD9 and regulates ubiquitination and subsequent degradation of NEDD9.[52] NEDD9 is also degraded by the proteasome at the end of mitosis, following completion of activities with Aurora-A that support mitotic progression.[46]

Tissue distribution and intracellular localization

In interphase cells, the majority of NEDD9 localizes to focal adhesions. However, some of the protein is also cytoplasmic, and small pools localize to the centrosome [39] and the basal body of cilia.[53] At mitotic entry NEDD9 moves along mitotic spindle, eventually localizing at midbody at cytokinesis.[39]

Function

NEDD9 mediated signaling

NEDD9 is an intermediate in a number of important signaling pathways relevant to the cellular processes of proliferation, survival, migration, and others (see figure to the right).[29][30][31]

Integrin, FAK/RAFTK, and SRC kinases

Integrin signaling, which control cell movement, spreading and adhesion to extracellular matrix (ECM), and survival, is the best established signaling pathway for NEDD9. Integrins are transmembrane proteins that nucleate focal adhesions, structures that provide bi-directional signaling between ECM and actin cytoskeleton. NEDD9 stabilizes formation and regulates turnover of focal adhesions, influencing cell motility and the invasion and metastasis of cancer cells.[54] In response to integrin activation, FAK or the related kinase RAFTK recruits NEDD9 into a focal adhesion site, binds it via the N-terminal SH3 domain and phosphorylates the NEDD9 Src-binding site. This allows SRC or SRC family kinase to bind NEDD9 via its SH2 domain. Phosphorylation of the NEDD9 substrate domain by Src and other kinases results in the creation of binding sites for Crk and other adaptors that associate with SH2 binding motifs. NEDD9 Crk complexes activate Rho and Ras family GTPases via the recruitment of their nucleotide exchange factors (GEFs), such as DOCK1, DOCK3 [32] DOCK180 and C3G.[55]

These GTPases regulate cell motility, proliferation and also contribute to tumor progression and invasion. In many cell types, NEDD9 overexpression increases spreading and crescent morphology (an indicator of high motility).[50] However, in fibroblasts, some work has found that absence of NEDD9 leads to more rapid focal adhesion turnover, which led to increase of migration in NEDD9-/- compared to wild type.[54]

In cancer cells, NEDD9 can drive mesenchymal-type movement by activating RAC1 GTPase and WAVE in complex with its GEF DOCK3, which in turn cause inhibition of GTPase Rho and amoeboid movement.[56] Invasion is accompanied by proteolysis of the ECM through activation of MMP14, MMP2 and MMP9 metalloproteinases.[57]

Chemokine receptors, TCR, BCR/ABL, Fyn, Lck kinases

NEDD9 is involved in chemokine-induced T cell migration and T cell receptor (TCR)–mediated integrin activation. In lymphocytes, integrin or TCR signaling induces NEDD9 phosphorylation by tyrosine kinases Fyn and Lck (SRC family kinases), which is essential for T cell migration.[58] In addition, in response to chemokine signals, Abl family kinases promote GTPase RAP1 activation by phosphorylating of NEDD9;[59] NEDD9 associates with the transducer protein Chat-H/SHEP1/NSP3, a member of the NSP protein family, further supporting RAP1 activation, cell migration, and adhesion.[60] In B cells, NEDD9 association with NSP3 enhances integrin-mediated NEDD9 serine/threonine hyperphosphorylation following B cell receptor (BCR) ligation, promoting B lymphocyte adhesion, motility and homing into marginal zones of spleen [61] Estrogen Receptor. The NEDD9 interactors p130/CAS and the NSP protein NSP2/BCAR3 are implicated in antiestrogen resistance [62][63] and breast cancer progression [64] Some data suggests a role for NEDD9 in the cellular response to estrogen, including the progression to anti-estrogen resistance, breast cancer progression and invasion [65][66][67]

RTKs (EGFR). NEDD9 also contributes to the transduction of signals downstream receptor tyrosine kinases (RTKs). A role for NEDD9 in signaling crosstalk between epidermal growth factor receptor (EGFR) and integrins was established in non-small lung cancer (NSLC). It was shown that inhibition of EGFR reduces the tyrosine phosphorylation of NEDD9.[68] Nedd9 interacts directly with the EGFR effector protein Shc, positioning it to affect downstream signaling relevant to EGFR; mice lacking Nedd9 have depressed activity of the EGFR effectors ERK and AKT.[69] NSP proteins are also multidomain scaffolds, which bind activated RTKs in response to extracellular stimuli and recruit both NEDD9 and BCAR1 to assist in integrating signaling between RTKs and integrins. NEDD9 is also activated by PDGF [70] and other RTKs, although more study is required.

TGF-beta

TGF-beta is a regulator of tissue remodeling and epithelial-mesenchymal transition (EMT) in development, and promotes metastasis in cancer. A number of studies have identified NEDD9 as a downstream effector in the TGF-beta signaling pathway, essential for promoting EMT.[17][51][71][72][73] In MCF-7 cells, NEDD9 negatively regulates expression of the epithelial protein E-cadherin, preventing association of E-cadherin with cell membrane and activating SRC-kinase.[74] Activated SRC provides internalization and lysosomal degradation of E-cadherin.[74] Consistent with these findings is a study demonstrating downregulation of epithelial markers (E-cadherin, occludin, β-catenin) and concurrent upregulation of mesenchymal markers (N-cadherin, vimentin, fibronectin) in response to NEDD9 overexpression in MCF-10 cells.[75]

Aurora-A

NEDD9 binds directly to the Aurora-A mitotic kinase at the centrosome, and promotes its activity, allowing cells to enter mitosis.[39][76] Degradation of NEDD9 at the end of mitosis contributes to timely Aurora-A degradation.[39][76][77] Cells overexpressing NEDD9 exhibit deficient cytokinesis resulting in the accumulation of multipolar mitotic spindles and abnormal numbers of centrosomes. On the other hand, cells with depleted NEDD9 have prematurely separated centrosomes and are deficient in microtubule organizing activity during mitosis, leading to an abundance of monopolar or asymmetric spindles,[39] preventing cells from entering mitosis. NEDD9 also regulates Aurora-A activation at the basal body of cilia as cells resorb cilia during early G1.[53] Cilia are small organelles that protrude from the surface of adherent cells that are the obligate site of action for proteins such as Hedgehog, and the polycystins: by influencing ciliary stability, NEDD9 is positioned to affect these signaling systems. Interaction of NEDD9 with Aurora A kinase may also play a role in tumor invasion. NEDD9 binds to and regulates acetylation of cortactin (CTTN) in an Aurora A kinase (AURKA)/HDAC6–dependent manner. The knockdown of NEDD9 or AURKA results in an increase in the amount of acetylated CTTN and a decrease in the binding of CTTN to F-actin. Overexpression of the deacetylation mimicking (9KR) mutant of CTTN is sufficient to restore actin dynamics at the leading edge and migration proficiency of the tumor cells. Inhibition of AURKA and HDAC6 activity by alisertib and tubastatin A in xenograft models of breast cancer has led to a decrease in the number of pulmonary metastases.[78]

Clinical significance

Transgenic mice with homozygous depletion of NEDD9 are vital and fertile, but have immunological abnormalities that result in pre-malignant conditions later in life, defects are initially subtle, but increase in later life; B cell homing to the spleen and lymphocyte trafficking are deficient.[69][79]

Alzheimer's disease

The NEDD9 rs760678 SNP located in an intronic region, has been studied for a possible association with late onset Alzheimer's disease (LOAD).[80][81][82][83][84] However, in 2012, Wang et al., performed a meta-analysis and concluded that more studies are required for solid conclusions.[83] This SNP and relevant signaling is discussed more fully in.[85]

Cancer

Altered (typically elevated) expression of NEDD9 is strongly associated with cancer. NEDD9 is rarely if ever mutated, but frequently show altered expression or phosphorylation (associated with increased activity) in pathological conditions including immune cell dysfunction and cancer. NEDD9 overexpression is documented to occur and in some cases linked the process of tumorigenesis of many different malignances. Besides examples in breast cancer discussed above, these malignancies include colon,[10][11][14][86] pancreatic,[87] head and neck,[88] ovarian,[89] gastric,[90] lung,[91] genitourinary (including prostate),[19][92] liver,[15] and kidney cancer,[13][20] gastrointestinal stromal tumors,[93] glioblastoma,[18][70][94] and neuroblastoma.[5][6][54]

Other disease

Nedd9 expression may be important for recovery from stroke. Nedd9 is upregulated in the neurons of the cerebral cortex and hippocampus after transient global ischemia in rats. Induced Nedd9 is tyrosine phosphorylated, bound to FAK in dendrite and soma of neurons, and promotes neurite outgrowth, contributing into recovery of neurologic function after cerebral ischemia.[95] Nedd9 has recently been implicated in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). NEDD9 expression is elevated in human autosomal dominant polycystic kidney disease (ADPKD) and in mouse ADPKD models, and ADPKD-prone mice lacking NEDD9 developed a more severe form of ADPKD than those with normal NEDD9.[96]

Therapeutic potential

Because of its roles in cancer, several studies have considered the potential value of NEDD9 as a therapeutic target or therapeutic guide. Because of lack of a kinase domain, or any defined catalytic domain, and because it is entirely intracellular, NEDD9 is a difficult molecule to target. Because NEDD9 serves as a scaffolding molecule for other signaling proteins that play significant roles in cancer development, the effects of NEDD9 overexpression in supporting metastasis could in theory be mitigated by inhibition of its downstream targets. In one study, deletion of Nedd9 in MMTV-neu mammary tumors increased their sensitivity to inhbitiors of FAK and SRC.[97] NEDD9 depletion sensitizes breast tumor cell lines to the Aurora A inhibitor alisertib.[77] Consideration of NEDD9 as a biomarker for therapeutic response is a promising research direction.

Interactions

NEDD9 has been shown to interact with:


Notes

References

  1. ↑ "Entrez Gene: NEDD9 neural precursor cell expressed, developmentally down-regulated 9". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4739. 
  2. ↑ "Identification of a set of genes with developmentally down-regulated expression in the mouse brain". Biochem. Biophys. Res. Commun. 185 (3): 1155–61. 1992. doi:10.1016/0006-291x(92)91747-e. PMID 1378265. 
  3. ↑ 3.0 3.1 "Human enhancer of filamentation 1, a novel p130cas-like docking protein, associates with focal adhesion kinase and induces pseudohyphal growth in Saccharomyces cerevisiae". Mol. Cell. Biol. 16 (7): 3327–37. 1996. doi:10.1128/mcb.16.7.3327. PMID 8668148. 
  4. ↑ 4.0 4.1 "Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta 1 integrin-mediated signaling in lymphocytes". J. Exp. Med. 184 (4): 1365–75. 1996. doi:10.1084/jem.184.4.1365. PMID 8879209. 
  5. ↑ 5.0 5.1 "All-trans retinoic acid-responsive genes identified in the human SH-SY5Y neuroblastoma cell line and their regulated expression in the nervous system of early embryos". Biol. Chem. 385 (7): 605–14. 2004. doi:10.1515/BC.2004.075. PMID 15318809. 
  6. ↑ 6.0 6.1 "Crk-associated substrate (Cas) family member, NEDD9, is regulated in human neuroblastoma cells and in the embryonic hindbrain by all-trans retinoic acid". Dev. Dyn. 231 (3): 564–75. 2004. doi:10.1002/dvdy.20159. PMID 15376324. 
  7. ↑ "A complex RARE is required for the majority of Nedd9 embryonic expression". Transgenic Res. 24 (1): 123–34. 2015. doi:10.1007/s11248-014-9825-9. PMID 25120220. 
  8. ↑ "Nedd9/Hef1/Cas-L mediates the effects of environmental pollutants on cell migration and plasticity". Oncogene 28 (41): 3642–51. 2009. doi:10.1038/onc.2009.224. PMID 19648964. 
  9. ↑ "SAFB1 mediates repression of immune regulators and apoptotic genes in breast cancer cells". J. Biol. Chem. 285 (6): 3608–16. 2010. doi:10.1074/jbc.M109.066431. PMID 19901029. 
  10. ↑ 10.0 10.1 "HEF1, a novel target of Wnt signaling, promotes colonic cell migration and cancer progression". Oncogene 30 (23): 2633–43. 2011. doi:10.1038/onc.2010.632. PMID 21317929. 
  11. ↑ 11.0 11.1 "Human enhancer of filamentation 1 Is a mediator of hypoxia-inducible factor-1alpha-mediated migration in colorectal carcinoma cells". Cancer Res. 70 (10): 4054–63. 2010. doi:10.1158/0008-5472.CAN-09-2110. PMID 20442290. 
  12. ↑ "Transcriptional profiling of human cord blood CD133+ and cultured bone marrow mesenchymal stem cells in response to hypoxia". Stem Cells 25 (4): 1003–12. 2007. doi:10.1634/stemcells.2006-0398. PMID 17185612. 
  13. ↑ 13.0 13.1 "VHL inactivation induces HEF1 and Aurora kinase A". J. Am. Soc. Nephrol. 21 (12): 2041–6. 2010. doi:10.1681/ASN.2010040345. PMID 20864688. 
  14. ↑ 14.0 14.1 "HEF1 is a crucial mediator of the proliferative effects of prostaglandin E(2) on colon cancer cells". Cancer Res. 70 (2): 824–31. 2010. doi:10.1158/0008-5472.CAN-09-2105. PMID 20068165. 
  15. ↑ 15.0 15.1 "Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma". Hepatology 57 (2): 610–24. 2013. doi:10.1002/hep.26029. PMID 22911555. 
  16. ↑ "The transcription factor PAX5 regulates its target genes by recruiting chromatin-modifying proteins in committed B cells". EMBO J. 30 (12): 2388–404. 2011. doi:10.1038/emboj.2011.140. PMID 21552207. 
  17. ↑ 17.0 17.1 "Regulation of HEF1 expression and phosphorylation by TGF-beta 1 and cell adhesion". J. Biol. Chem. 277 (42): 39599–608. 2002. doi:10.1074/jbc.M202263200. PMID 12189134. 
  18. ↑ 18.0 18.1 "NEDD9, a novel target of miR-145, increases the invasiveness of glioblastoma". Oncotarget 3 (7): 723–34. 2012. doi:10.18632/oncotarget.547. PMID 22869051. 
  19. ↑ 19.0 19.1 "HEF1 promotes epithelial mesenchymal transition and bone invasion in prostate cancer under the regulation of microRNA-145". J. Cell. Biochem. 114 (7): 1606–15. 2013. doi:10.1002/jcb.24502. PMID 23355420. 
  20. ↑ 20.0 20.1 "miR-145 functions as tumor suppressor and targets two oncogenes, ANGPT2 and NEDD9, in renal cell carcinoma". J. Cancer Res. Clin. Oncol. 140 (3): 387–97. 2014. doi:10.1007/s00432-013-1577-z. PMID 24384875. 
  21. ↑ "A novel large regulator RNA, B2, partially overlaps the HEF1/NEDD9/Cas-L gene". Int. J. Mol. Med. 25 (6): 897–903. 2010. doi:10.3892/ijmm_00000420. PMID 20428794. 
  22. ↑ "Differential expression and dynamic changes of murine NEDD9 in progenitor cells of diverse tissues". Gene Expr. Patterns 8 (4): 217–26. 2008. doi:10.1016/j.gep.2008.01.001. PMID 18282814. 
  23. ↑ "A novel signaling molecule, p130, forms stable complexes in vivo with v-Crk and v-Src in a tyrosine phosphorylation-dependent manner". EMBO J. 13 (16): 3748–56. 1994. doi:10.1002/j.1460-2075.1994.tb06684.x. PMID 8070403. 
  24. ↑ "Molecular cloning of a cDNA encoding a phosphoprotein, Efs, which contains a Src homology 3 domain and associates with Fyn". Oncogene 11 (11): 2331–8. 1995. PMID 8570184. 
  25. ↑ "Proline-rich sequences that bind to Src homology 3 domains with individual specificities". Proc. Natl. Acad. Sci. U.S.A. 92 (8): 3110–4. 1995. doi:10.1073/pnas.92.8.3110. PMID 7536925. Bibcode: 1995PNAS...92.3110A. 
  26. ↑ "A novel Cas family member, HEPL, regulates FAK and cell spreading". Mol. Biol. Cell 19 (4): 1627–36. 2008. doi:10.1091/mbc.E07-09-0953. PMID 18256281. 
  27. ↑ "Crk-associated substrate (Cas) signaling protein functions with integrins to specify axon guidance during development". Development 134 (12): 2337–47. 2007. doi:10.1242/dev.004242. PMID 17537798. 
  28. ↑ "Dcas supports cell polarization and cell-cell adhesion complexes in development". PLOS ONE 5 (8): e12369. 2010. doi:10.1371/journal.pone.0012369. PMID 20808771. Bibcode: 2010PLoSO...512369T. 
  29. ↑ 29.0 29.1 "CAS proteins in health and disease: an update". IUBMB Life 66 (6): 387–95. 2014. doi:10.1002/iub.1282. PMID 24962474. 
  30. ↑ 30.0 30.1 30.2 "Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle". Cell Biochem. Biophys. 48 (1): 54–72. 2007. doi:10.1007/s12013-007-0036-3. PMID 17703068. 
  31. ↑ 31.0 31.1 31.2 "CAS proteins in normal and pathological cell growth control". Cell. Mol. Life Sci. 67 (7): 1025–48. 2010. doi:10.1007/s00018-009-0213-1. PMID 19937461. 
  32. ↑ 32.0 32.1 32.2 32.3 "Integrin signalling adaptors: not only figurants in the cancer story". Nat. Rev. Cancer 10 (12): 858–70. 2010. doi:10.1038/nrc2967. PMID 21102636. 
  33. ↑ "Integrin signalling: a new Cas(t) of characters enters the stage". Trends Cell Biol. 10 (3): 111–9. 2000. doi:10.1016/s0962-8924(99)01714-6. PMID 10675905. 
  34. ↑ "Direct binding of p130(Cas) to the guanine nucleotide exchange factor C3G". J. Biol. Chem. 273 (40): 25673–9. 1998. doi:10.1074/jbc.273.40.25673. PMID 9748234. 
  35. ↑ "Association of PTP-PEST with the SH3 domain of p130cas; a novel mechanism of protein tyrosine phosphatase substrate recognition". Oncogene 15 (8): 877–85. 1997. doi:10.1038/sj.onc.1201279. PMID 9285683. 
  36. ↑ "Direct binding of the proline-rich region of protein tyrosine phosphatase 1B to the Src homology 3 domain of p130(Cas)". J. Biol. Chem. 271 (49): 31290–5. 1996. doi:10.1074/jbc.271.49.31290. PMID 8940134. 
  37. ↑ "CIZ, a zinc finger protein that interacts with p130(cas) and activates the expression of matrix metalloproteinases". Mol. Cell. Biol. 20 (5): 1649–58. 2000. doi:10.1128/mcb.20.5.1649-1658.2000. PMID 10669742. 
  38. ↑ "Activation of a signaling cascade by cytoskeleton stretch". Dev. Cell 7 (5): 709–18. 2004. doi:10.1016/j.devcel.2004.08.021. PMID 15525532. 
  39. ↑ 39.0 39.1 39.2 39.3 39.4 39.5 39.6 "The focal adhesion scaffolding protein HEF1 regulates activation of the Aurora-A and Nek2 kinases at the centrosome". Nat. Cell Biol. 7 (10): 937–46. 2005. doi:10.1038/ncb1309. PMID 16184168. 
  40. ↑ "The serine-rich domain from Crk-associated substrate (p130cas) is a four-helix bundle". J. Biol. Chem. 280 (23): 21908–14. 2005. doi:10.1074/jbc.M501258200. PMID 15795225. 
  41. ↑ "The structural basis of localization and signaling by the focal adhesion targeting domain". Structure 10 (3): 319–27. 2002. doi:10.1016/s0969-2126(02)00717-7. PMID 12005431. 
  42. ↑ "The focal adhesion targeting (FAT) region of focal adhesion kinase is a four-helix bundle that binds paxillin". Nat. Struct. Biol. 9 (2): 101–6. 2002. doi:10.1038/nsb755. PMID 11799401. 
  43. ↑ "NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer". Genes Cancer 3 (5–6): 382–93. 2012. doi:10.1177/1947601912460050. PMID 23226576. 
  44. ↑ "NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling". Nat. Struct. Mol. Biol. 18 (12): 1381–7. 2011. doi:10.1038/nsmb.2152. PMID 22081014. 
  45. ↑ "Dimerization of the docking/adaptor protein HEF1 via a carboxy-terminal helix-loop-helix domain". Exp. Cell Res. 252 (1): 224–35. 1999. doi:10.1006/excr.1999.4609. PMID 10502414. 
  46. ↑ 46.0 46.1 46.2 46.3 "Cell cycle-regulated processing of HEF1 to multiple protein forms differentially targeted to multiple subcellular compartments". Mol. Cell. Biol. 18 (6): 3540–51. 1998. doi:10.1128/MCB.18.6.3540. PMID 9584194. 
  47. ↑ 47.0 47.1 "Cell adhesion regulates Ser/Thr phosphorylation and proteasomal degradation of HEF1". J. Cell Sci. 119 (Pt 1): 96–103. 2006. doi:10.1242/jcs.02712. PMID 16352661. 
  48. ↑ "PP2A phosphatase suppresses function of the mesenchymal invasion regulator NEDD9". Biochim. Biophys. Acta 1823 (2): 290–7. 2012. doi:10.1016/j.bbamcr.2011.10.011. PMID 22061964. 
  49. ↑ "The docking protein HEF1 is an apoptotic mediator at focal adhesion sites". Mol. Cell. Biol. 20 (14): 5184–95. 2000. doi:10.1128/mcb.20.14.5184-5195.2000. PMID 10866674. 
  50. ↑ 50.0 50.1 50.2 "Proteolysis of the docking protein HEF1 and implications for focal adhesion dynamics". Mol. Cell. Biol. 21 (15): 5094–108. 2001. doi:10.1128/MCB.21.15.5094-5108.2001. PMID 11438665. 
  51. ↑ 51.0 51.1 "A novel ability of Smad3 to regulate proteasomal degradation of a Cas family member HEF1". EMBO J. 19 (24): 6759–69. 2000. doi:10.1093/emboj/19.24.6759. PMID 11118211. 
  52. ↑ "Direct interaction between Smad3, APC10, CDH1 and HEF1 in proteasomal degradation of HEF1". BMC Cell Biol. 5: 20. 2004. doi:10.1186/1471-2121-5-20. PMID 15144564. 
  53. ↑ 53.0 53.1 "HEF1-dependent Aurora A activation induces disassembly of the primary cilium". Cell 129 (7): 1351–63. 2007. doi:10.1016/j.cell.2007.04.035. PMID 17604723. 
  54. ↑ 54.0 54.1 54.2 "NEDD9 stabilizes focal adhesions, increases binding to the extra-cellular matrix and differentially effects 2D versus 3D cell migration". PLOS ONE 7 (4): e35058. 2012. doi:10.1371/journal.pone.0035058. PMID 22509381. Bibcode: 2012PLoSO...735058Z. 
  55. ↑ "Cas and NEDD9 Contribute to Tumor Progression through Dynamic Regulation of the Cytoskeleton". Genes Cancer 3 (5–6): 371–81. 2012. doi:10.1177/1947601912458585. PMID 23226575. 
  56. ↑ "Rac activation and inactivation control plasticity of tumor cell movement". Cell 135 (3): 510–23. 2008. doi:10.1016/j.cell.2008.09.043. PMID 18984162. 
  57. ↑ "NEDD9 depletion leads to MMP14 inactivation by TIMP2 and prevents invasion and metastasis". Mol. Cancer Res. 12 (1): 69–81. 2014. doi:10.1158/1541-7786.MCR-13-0300. PMID 24202705. 
  58. ↑ "Fyn and Lck tyrosine kinases regulate tyrosine phosphorylation of p105CasL, a member of the p130Cas docking protein family, in T-cell receptor-mediated signalling". Immunology 97 (1): 56–61. 1999. doi:10.1046/j.1365-2567.1999.00753.x. PMID 10447714. 
  59. ↑ "Tyrosine kinases EnAbling adaptor molecules for chemokine-induced Rap1 activation in T cells". Sci Signal 5 (235): pe33. 2012. doi:10.1126/scisignal.2003383. PMID 22855504. 
  60. ↑ 60.0 60.1 "The hematopoietic isoform of Cas-Hef1-associated signal transducer regulates chemokine-induced inside-out signaling and T cell trafficking". Immunity 25 (6): 907–18. 2006. doi:10.1016/j.immuni.2006.09.014. PMID 17174122. 
  61. ↑ "SHEP1 partners with CasL to promote marginal zone B-cell maturation". Proc. Natl. Acad. Sci. U.S.A. 107 (44): 18944–9. 2010. doi:10.1073/pnas.1007558107. PMID 20956287. Bibcode: 2010PNAS..10718944B. 
  62. ↑ "Association of the breast cancer antiestrogen resistance protein 1 (BCAR1) and BCAR3 scaffolding proteins in cell signaling and antiestrogen resistance". J. Biol. Chem. 289 (15): 10431–44. 2014. doi:10.1074/jbc.M113.541839. PMID 24584939. 
  63. ↑ "BCAR1, a human homologue of the adapter protein p130Cas, and antiestrogen resistance in breast cancer cells". J. Natl. Cancer Inst. 92 (2): 112–20. 2000. doi:10.1093/jnci/92.2.112. PMID 10639512. 
  64. ↑ "The interaction between caveolin-1 and Rho-GTPases promotes metastasis by controlling the expression of alpha5-integrin and the activation of Src, Ras and Erk". Oncogene 31 (7): 884–96. 2012. doi:10.1038/onc.2011.288. PMID 21765460. 
  65. ↑ "Protein pathway activation mapping reveals molecular networks associated with antiestrogen resistance in breast cancer cell lines". Int. J. Cancer 131 (9): 1998–2007. 2012. doi:10.1002/ijc.27489. PMID 22328489. 
  66. ↑ "Structural insights into the association between BCAR3 and Cas family members, an atypical complex implicated in anti-oestrogen resistance". J. Mol. Biol. 386 (1): 190–203. 2009. doi:10.1016/j.jmb.2008.12.010. PMID 19103205. 
  67. ↑ "Estradiol stabilizes the 105-kDa phospho-form of the adhesion docking protein NEDD9 and suppresses NEDD9-dependent cell spreading in breast cancer cells". Biochim. Biophys. Acta 1813 (2): 340–5. 2011. doi:10.1016/j.bbamcr.2010.11.018. PMID 21145356. 
  68. ↑ "Impact of the integrin signaling adaptor protein NEDD9 on prognosis and metastatic behavior of human lung cancer". Clin. Cancer Res. 18 (22): 6326–38. 2012. doi:10.1158/1078-0432.CCR-11-2162. PMID 23037767. 
  69. ↑ 69.0 69.1 "NEDD9 promotes oncogenic signaling in mammary tumor development". Cancer Res. 69 (18): 7198–206. 2009. doi:10.1158/0008-5472.CAN-09-0795. PMID 19738060. 
  70. ↑ 70.0 70.1 "HEF1 is a necessary and specific downstream effector of FAK that promotes the migration of glioblastoma cells". Oncogene 25 (12): 1721–32. 2006. doi:10.1038/sj.onc.1209199. PMID 16288224. 
  71. ↑ "Crk-associated substrate lymphocyte type regulates transforming growth factor-beta signaling by inhibiting Smad6 and Smad7". Oncogene 26 (6): 893–904. 2007. doi:10.1038/sj.onc.1209848. PMID 16909115. 
  72. ↑ "Transforming growth factor beta promotes neuronal cell fate of mouse cortical and hippocampal progenitors in vitro and in vivo: identification of Nedd9 as an essential signaling component". Cereb. Cortex 20 (3): 661–71. 2010. doi:10.1093/cercor/bhp134. PMID 19587023. 
  73. ↑ "Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility". Nat. Cell Biol. 11 (11): 1287–96. 2009. doi:10.1038/ncb1973. PMID 19838175. 
  74. ↑ 74.0 74.1 "NEDD9 and BCAR1 negatively regulate E-cadherin membrane localization, and promote E-cadherin degradation". PLOS ONE 6 (7): e22102. 2011. doi:10.1371/journal.pone.0022102. PMID 21765937. Bibcode: 2011PLoSO...622102T. 
  75. ↑ "NEDD9 is a positive regulator of epithelial-mesenchymal transition and promotes invasion in aggressive breast cancer". PLOS ONE 6 (7): e22666. 2011. doi:10.1371/journal.pone.0022666. PMID 21829474. Bibcode: 2011PLoSO...622666K. 
  76. ↑ 76.0 76.1 76.2 "HEF1-aurora A interactions: points of dialog between the cell cycle and cell attachment signaling networks". Cell Cycle 5 (4): 384–91. 2006. doi:10.4161/cc.5.4.2439. PMID 16479169. 
  77. ↑ 77.0 77.1 "NEDD9 depletion destabilizes Aurora A kinase and heightens the efficacy of Aurora A inhibitors: implications for treatment of metastatic solid tumors". Cancer Res. 73 (10): 3168–80. 2013. doi:10.1158/0008-5472.CAN-12-4008. PMID 23539442. 
  78. ↑ "NEDD9 regulates actin dynamics through cortactin deacetylation in an AURKA/HDAC6-dependent manner". Mol. Cancer Res. 12 (5): 681–93. 2014. doi:10.1158/1541-7786.MCR-13-0654. PMID 24574519. 
  79. ↑ "Crk-associated substrate lymphocyte type is required for lymphocyte trafficking and marginal zone B cell maintenance". J. Immunol. 175 (6): 3492–501. 2005. doi:10.4049/jimmunol.175.6.3492. PMID 16148091. 
  80. ↑ "Association study of the NEDD9 gene with the risk of developing Alzheimer's and Parkinson's disease". Hum. Mol. Genet. 17 (18): 2863–7. 2008. doi:10.1093/hmg/ddn183. PMID 18579580. 
  81. ↑ "Evidence that common variation in NEDD9 is associated with susceptibility to late-onset Alzheimer's and Parkinson's disease". Hum. Mol. Genet. 17 (5): 759–67. 2008. doi:10.1093/hmg/ddm348. PMID 18063669. 
  82. ↑ "Different implication of NEDD9 genetic variant in early and late-onset Alzheimer's disease". Neurosci. Lett. 477 (3): 121–3. 2010. doi:10.1016/j.neulet.2010.04.046. PMID 20430066. 
  83. ↑ 83.0 83.1 "NEDD9 rs760678 polymorphism and the risk of Alzheimer's disease: a meta-analysis". Neurosci. Lett. 527 (2): 121–5. 2012. doi:10.1016/j.neulet.2012.08.044. PMID 22963925. 
  84. ↑ "NEDD9 is genetically associated with Alzheimer's disease in a Han Chinese population". Brain Res. 1369: 230–4. 2011. doi:10.1016/j.brainres.2010.10.113. PMID 21059344. 
  85. ↑ Beck, T.N. (2014). "Adaptors for disorders of the brain? The cancer signaling proteins NEDD9, CASS4, and PTK2B in Alzheimer's disease.". Oncoscience 1 (Oncoscience, 2014. 1(7): p. 486–503): 486–503. doi:10.18632/oncoscience.64. PMID 25594051. 
  86. ↑ "High expression of NEDD9 predicts adverse outcomes of colorectal cancer patients". Int J Clin Exp Pathol 7 (5): 2565–70. 2014. PMID 24966970. 
  87. ↑ "Expression of NEDD9 in pancreatic ductal adenocarcinoma and its clinical significance". Tumour Biol. 34 (2): 895–9. 2013. doi:10.1007/s13277-012-0624-8. PMID 23247867. 
  88. ↑ "Regulation of invasive behavior by vascular endothelial growth factor is HEF1-dependent". Oncogene 29 (31): 4449–59. 2010. doi:10.1038/onc.2010.185. PMID 20498643. 
  89. ↑ "NEDD9 overexpression is associated with the progression of and an unfavorable prognosis in epithelial ovarian cancer". Hum. Pathol. 45 (2): 401–8. 2014. doi:10.1016/j.humpath.2013.10.005. PMID 24439227. 
  90. ↑ "Overexpression of Nedd9 is a prognostic marker of human gastric cancer". Med. Oncol. 31 (7): 33. 2014. doi:10.1007/s12032-014-0033-5. PMID 24906654. 
  91. ↑ "NEDD9 promotes lung cancer metastasis through epithelial-mesenchymal transition". Int. J. Cancer 134 (10): 2294–304. 2014. doi:10.1002/ijc.28568. PMID 24174333. 
  92. ↑ "NEDD9 crucially regulates TGF-β-triggered epithelial-mesenchymal transition and cell invasion in prostate cancer cells: involvement in cancer progressiveness". Prostate 74 (8): 901–10. 2014. doi:10.1002/pros.22809. PMID 24728978. 
  93. ↑ "Cas-L was overexpressed in imatinib-resistant gastrointestinal stromal tumor cells". Cancer Biol. Ther. 8 (8): 683–8. 2009. doi:10.4161/cbt.8.8.7779. PMID 19417561. 
  94. ↑ "Overexpression of s6 kinase 1 in brain tumours is associated with induction of hypoxia-responsive genes and predicts patients' survival". J Oncol 2012: 1–10. 2012. doi:10.1155/2012/416927. PMID 22570651. 
  95. ↑ "Nedd9 protein, a Cas-L homologue, is upregulated after transient global ischemia in rats: possible involvement of Nedd9 in the differentiation of neurons after ischemia". Stroke 36 (11): 2457–62. 2005. doi:10.1161/01.STR.0000185672.10390.30. PMID 16210561. 
  96. ↑ "Nedd9 restrains renal cystogenesis in Pkd1-/- mice". Proc. Natl. Acad. Sci. U.S.A. 111 (35): 12859–64. 2014. doi:10.1073/pnas.1405362111. PMID 25139996. Bibcode: 2014PNAS..11112859N. 
  97. ↑ "A requirement for Nedd9 in luminal progenitor cells prior to mammary tumorigenesis in MMTV-HER2/ErbB2 mice". Oncogene 33 (4): 411–20. 2014. doi:10.1038/onc.2012.607. PMID 23318423. 
  98. ↑ 98.0 98.1 98.2 "Structure and function of Cas-L, a 105-kD Crk-associated substrate-related protein that is involved in beta 1 integrin-mediated signaling in lymphocytes". J. Exp. Med. 184 (4): 1365–75. October 1996. doi:10.1084/jem.184.4.1365. PMID 8879209. 
  99. ↑ 99.0 99.1 "Human enhancer of filamentation 1, a novel p130cas-like docking protein, associates with focal adhesion kinase and induces pseudohyphal growth in Saccharomyces cerevisiae". Mol. Cell. Biol. 16 (7): 3327–37. July 1996. doi:10.1128/mcb.16.7.3327. PMID 8668148. 
  100. ↑ 100.0 100.1 "Direct interaction between Smad3, APC10, CDH1 and HEF1 in proteasomal degradation of HEF1". BMC Cell Biol. 5: 20. May 2004. doi:10.1186/1471-2121-5-20. PMID 15144564. 
  101. ↑ "T cell receptor-mediated tyrosine phosphorylation of Cas-L, a 105-kDa Crk-associated substrate-related protein, and its association of Crk and C3G". J. Biol. Chem. 273 (11): 6446–51. March 1998. doi:10.1074/jbc.273.11.6446. PMID 9497377. 
  102. ↑ 102.0 102.1 "Involvement of p130(Cas) and p105(HEF1), a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells". J. Biol. Chem. 272 (7): 4230–6. February 1997. doi:10.1074/jbc.272.7.4230. PMID 9020138. 
  103. ↑ "Differential interaction of Crkl with Cbl or C3G, Hef-1, and gamma subunit immunoreceptor tyrosine-based activation motif in signaling of myeloid high affinity Fc receptor for IgG (Fc gamma RI)". J. Immunol. 161 (10): 5555–63. November 1998. doi:10.4049/jimmunol.161.10.5555. PMID 9820532. 
  104. ↑ "Association of the Cas-like molecule HEF1 with CrkL following integrin and antigen receptor signaling in human B-cells: potential relevance to neoplastic lymphohematopoietic cells". Leuk. Lymphoma 28 (1–2): 65–72. December 1997. doi:10.3109/10428199709058332. PMID 9498705. 
  105. ↑ "Differential signaling after beta1 integrin ligation is mediated through binding of CRKL to p120(CBL) and p110(HEF1)". J. Biol. Chem. 272 (22): 14320–6. May 1997. doi:10.1074/jbc.272.22.14320. PMID 9162067. 
  106. ↑ "Dimerization of the docking/adaptor protein HEF1 via a carboxy-terminal helix-loop-helix domain". Exp. Cell Res. 252 (1): 224–35. October 1999. doi:10.1006/excr.1999.4609. PMID 10502414. 
  107. ↑ "MICAL, a novel CasL interacting molecule, associates with vimentin". J. Biol. Chem. 277 (17): 14933–41. April 2002. doi:10.1074/jbc.M111842200. PMID 11827972. 
  108. ↑ "Atrophin-1-interacting protein 4/human Itch is a ubiquitin E3 ligase for human enhancer of filamentation 1 in transforming growth factor-beta signaling pathways". J. Biol. Chem. 279 (28): 29681–90. July 2004. doi:10.1074/jbc.M403221200. PMID 15051726. 
  109. ↑ "A novel ability of Smad3 to regulate proteasomal degradation of a Cas family member HEF1". EMBO J. 19 (24): 6759–69. December 2000. doi:10.1093/emboj/19.24.6759. PMID 11118211. 



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