Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''NEDD9''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
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
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
of this gene is
BCAR1
Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the ''BCAR1'' gene.
Gene
BCAR1 is localized on chromosome 16 on region q, on the negative strand and it consists of seven exons. Eight different gene is ...
.
Discovery
In 1992, Kumar, ''et al.,'' first described a sequence tag corresponding to the NEDD9 3′ untranslated region based on the
cloning
Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, c ...
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
PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the ''PTK2'' gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to ...
(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
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
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).
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
The Human Genome Organisation (HUGO) is a non-profit organization founded in 1988. HUGO represents an international coordinating scientific body in response to initiatives such as the Human Genome Project. HUGO has four active committees, includin ...
(HUGO) gene nomenclature committee (
HGNC
The HUGO Gene Nomenclature Committee (HGNC) is a committee of the Human Genome Organisation (HUGO) that sets the standards for human gene nomenclature. The HGNC approves a ''unique'' and ''meaningful'' name for every known human gene, based on a q ...
). 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
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
, and frogs. In vertebrates, it is a member of a 4-gene family, with the other paralogous genes known as
BCAR1
Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the ''BCAR1'' gene.
Gene
BCAR1 is localized on chromosome 16 on region q, on the negative strand and it consists of seven exons. Eight different gene is ...
(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
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
(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
Tretinoin, also known as all-''trans'' retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For leukemia, it is taken by mouth f ...
(ATRA), and contains a retinoic acid response element (RARE) that is specifically bound by a
retinoid X receptor
The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-''cis''-13,14-dihydroretinoic acid, which is likely to be the major e ...
(RXR)/retinoic acid receptor (RAR)
heterodimer.
NEDD9 is also induced by the environmental pollutant
dioxin, based on regulation through the
aryl hydrocarbon receptor
The aryl hydrocarbon receptor (also known as AhR, AHR, ahr, ahR, or dioxin receptor) is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a transcription factor that regulates gene expression. It was originall ...
(AhR).
One study has found NEDD9 repressed by
estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
, based on binding of the SAFB1 co-repressor.
NEDD9 is induced by
Wnt signaling
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. 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 factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s to the NEDD9 promoter.
Prostaglandin E2 induces NEDD9 transcription.
The Fox transcription factor Forkhead box C1 (
FoxC1)
and
PAX5
Paired box protein Pax-5 is a protein that in humans is encoded by the ''PAX5'' gene.
Function
The PAX5 gene is a member of the paired box (PAX) family of transcription factors. The central feature of this gene family is a novel, highly cons ...
transcription factor
have been reported to induce NEDD9 transcription.
TGF-beta
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
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
Signal transducer and activator of transcription 5A is a protein that in humans is encoded by the ''STAT5A'' gene. ''STAT5A'' orthologs have been identified in several placentals for which complete genome data are available.
Structure
STAT5a s ...
and
NF-kappa B.
In the
3'UTR
In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...
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
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...
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
A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non ...
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.
Protein family
NEDD9 is a member of the
CAS (Crk-associated substrate) protein family, which has 4 members in vertebrates. The other
paralogous
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
genes are known
BCAR1
Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the ''BCAR1'' gene.
Gene
BCAR1 is localized on chromosome 16 on region q, on the negative strand and it consists of seven exons. Eight different gene is ...
(p130Cas),
EFS (Sin),
and
CASS4
Cas scaffolding protein family member 4 is a protein that in humans is encoded by the CASS4 gene.
History and discovery
CASS4 (Crk associated substrate 4) is the fourth and last described member of the CAS protein family. CASS4 was detected by ...
(HEPL).
There is no detectable NEDD9-related gene in bacteria, yeast, or ''
C. elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
''. A single family member exists in ''
D. Melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
'', termed DCas.
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
The overall structure of NEDD9 is represented graphically in Figure 1.
![Figure 1 NEDD9 structure](https://upload.wikimedia.org/wikipedia/commons/7/7c/Figure_1_NEDD9_structure.jpg)
These domains include:
; SH3 domain: This highly conserved
N-terminal domain mediates NEDD9 binding to the
polyproline
A polyproline helix is a type of protein secondary structure which occurs in proteins comprising repeating proline residues. A left-handed polyproline II helix (PPII, poly-Pro II) is formed when sequential residues all adopt (φ,ψ) backbone dihedr ...
motifs of a number of important interacting proteins, with some well-studied partners being
FAK and the related
PYK2
Protein tyrosine kinase 2 beta is an enzyme that in humans is encoded by the ''PTK2B'' gene.
Function
This gene encodes a cytoplasmic protein tyrosine kinase that is involved in calcium-induced regulation of ion channels and activation of the ...
/RAFTK kinase,
C3G,
PTP-PEST,
PTP1B
Tyrosine-protein phosphatase non-receptor type 1 also known as protein-tyrosine phosphatase 1B (PTP1B) is an enzyme that is the founding member of the protein tyrosine phosphatase (PTP) family. In humans it is encoded by the ''PTPN1'' gene. PTP1B i ...
and
CIZ.
; Substrate domain (SD): This unstructured region contains multiple YxxP motifs, which are
phosphorylated
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
by
src family kinase
Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs ...
s (such as
FYN
Funen ( da, Fyn, ), with an area of , is the third-largest island of Denmark, after Zealand and Vendsyssel-Thy. It is the 165th-largest island in the world. It is located in the central part of the country and has a population of 469,947 as ...
,
LCK
Lck (or lymphocyte-specific protein tyrosine kinase) is a 56 kDa protein that is found inside specialized cells of the immune system called lymphocytes. The Lck is a member of Src kinase family (SFK), it is important for the activation of the T ...
and
SRC) to create binding sites for proteins with SH2 domains, such as Crk.
Phosphorylation of these motifs can be activated by mechanical forces such as
cytoskeletal
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compo ...
stretch.
Other phosphorylation events in this region are imposed by the kinase Aurora-A, which phosphorylates residue S296, for processes related to cell cycle control.
; 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.
; Focal adhesion targeting (FAT) domain: The FAT-like
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
domain
is highly conserved in
focal adhesion
In cell biology, focal adhesions (also cell–matrix adhesions or FAs) are large macromolecular assemblies through which mechanical force and regulatory signals are transmitted between the extracellular matrix (ECM) and an interacting cell. More ...
proteins, and sufficient for localizing
focal adhesion kinase
PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the ''PTK2'' gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to ...
(FAK) to focal adhesions.
It forms a four-helix bundle structure and implicated in interaction with NSP proteins (novel SH2-containing protein family),
and other proteins such as the Id family of helix-loop-helix proteins.
In terms of
post-translational modification
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribos ...
s, 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
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
cells,
suggesting these modifications are associated with increased localization to
centrosome
In cell biology, the centrosome (Latin centrum 'center' + Greek sōma 'body') (archaically cytocentre) is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle prog ...
and
mitotic spindle
In cell biology, the spindle apparatus refers to the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a pr ...
. One study indicated the conversion of p115 into p105 is activated by cell detachment through cytoskeletal regulation of phosphatase
PP2A
Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in eu ...
,
although other work has found conflicting results.
Synthesis and degradation
NEDD9 is present throughout
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
, but most abundant in G2/M phase cells.
NEDD9 is subject to both
caspase cleavage and
proteasomal degradation.
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)
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.
Overexpression of p28 in cells causes cellular rounding and detachment, and induces apoptosis,
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.
Proteasomal degradation of NEDD9 is triggered by a number of stimuli, including induction of TGF-beta signaling.
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.
NEDD9 is also degraded by the proteasome at the end of mitosis, following completion of activities with Aurora-A that support mitotic progression.
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
and the basal body of cilia.
At mitotic entry NEDD9 moves along mitotic spindle, eventually localizing at midbody at cytokinesis.
Function
![Figure 2 NEDD9 mediated signaling](https://upload.wikimedia.org/wikipedia/commons/f/fb/Figure_2_NEDD9_mediated_signaling.png)
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).
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.
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
DOCK180 and C3G.
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).
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.
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.
Invasion is accompanied by proteolysis of the ECM through activation of MMP14, MMP2 and MMP9 metalloproteinases.
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.
In addition, in response to chemokine signals, Abl family kinases promote GTPase RAP1 activation by phosphorylating of NEDD9;
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.
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
Estrogen Receptor. The NEDD9 interactors p130/CAS and the NSP protein NSP2/BCAR3 are implicated in antiestrogen resistance
and breast cancer progression
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
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.
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.
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
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.
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.
Activated SRC provides internalization and lysosomal degradation of E-cadherin.
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.
Aurora-A
NEDD9 binds directly to the Aurora-A mitotic kinase at the centrosome, and promotes its activity, allowing cells to enter mitosis.
Degradation of NEDD9 at the end of mitosis contributes to timely Aurora-A degradation.
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,
preventing cells from entering mitosis. NEDD9 also regulates Aurora-A activation at the basal body of cilia as cells resorb cilia during early G1.
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.
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.
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).
However, in 2012, Wang ''et al.,'' performed a meta-analysis and concluded that more studies are required for solid conclusions.
This SNP and relevant signaling is discussed more fully in.
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,
pancreatic,
head and neck,
ovarian,
gastric,
lung,
genitourinary (including prostate),
liver,
and kidney cancer,
gastrointestinal stromal tumors,
glioblastoma,
and neuroblastoma.
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.
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.
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.
NEDD9 depletion sensitizes breast tumor cell lines to the Aurora A inhibitor alisertib.
Consideration of NEDD9 as a biomarker for therapeutic response is a promising research direction.
Interactions
NEDD9 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
ABL1
Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ''ABL1'' gene (previous symbol ''ABL'') located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian ...
,
* AURKA
Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the ''AURKA'' gene.
Aurora A is a member of a family of mitotic serine/threonine kinases. It is implicated with important processes during m ...
,
* CDH1,
* CRK,
* CRKL
Crk-like protein is a protein that in humans is encoded by the CRKL gene.
Function
v-CRK avian sarcoma virus CT10-homolog-like contains one SH2 domain and two SH3 domains. CRKL has been shown to activate the RAS and JUN kinase signaling pathw ...
,
* ID2
DNA-binding protein inhibitor ID-2 is a protein that in humans is encoded by the ''ID2'' gene.
Function
The protein encoded by this gene belongs to the inhibitor of DNA binding (ID) family, members of which are transcriptional regulators that ...
,
* LYN,
* MICAL1
NEDD9-interacting protein with calponin homology and LIM domains is a protein that in humans is encoded by the ''MICAL1'' gene.
Interactions
MICAL1 has been shown to interact with NEDD9 and RAB1A
Ras-related protein Rab-1A is a protein that in ...
,
* NCK1
Cytoplasmic protein NCK1 is a protein that in humans is encoded by the ''NCK1'' gene.
Gene
The Nck (non-catalytic region of tyrosine kinase adaptor protein 1) belongs to the adaptor family of proteins. The nck gene was initially isolated from ...
,
* NSP,
* PTK2
PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the ''PTK2'' gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick ...
,[
* ]SMAD3
Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.
SMAD3 is a member of the SMAD family of proteins. It acts as a mediator of the signals initiated by t ...
, and
* SRC.
Notes
References
{{reflist, 35em
Genes
Human proteins