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CDCP1 (CUB domain containing protein 1)

Written2013-06Mark Moasser, Danislav Spassov
Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)CD318
SIMA135
Other aliasTRASK
HGNC (Hugo) CDCP1
LocusID (NCBI) 64866
Atlas_Id 40016
Location 3p21.31  [Link to chromosome band 3p21]
Location_base_pair Starts at 45082274 and ends at 45146422 bp from pter ( according to hg19-Feb_2009)  [Mapping CDCP1.png]
Fusion genes
(updated 2016)
CDCP1 (3p21.31) / CAMLG (5q31.1)CDCP1 (3p21.31) / CDCP1 (3p21.31)CDCP1 (3p21.31) / KPNB1 (17q21.32)

DNA/RNA

Note CDCP1 (CUB Domain Containing Protein) was independently identified by several research groups. CDCP1 was initially isolated as a gene expressed in colorectal cancer (Scherl-Mostageer et al.,2001). The CDCP1 gene product was independently identified as a protein phosphorylated during mitosis and cellular detachment by Src kinases (Bhatt et al., 2005) and it is also known as Trask (Transmembrane and Associated with Src Kinases).
Description The CDCP1 gene comprises 9 verified exons.
Transcription Two alternative transcripts have been described (Perry et al., 2007). The full length transcript (isoform 1) is approximately 6.4 kb in length, spans all 9 exons and encodes a transmembrane protein. The isoform 2 transcript is 1.4 kb in length, contains the first four 5'exons of the CDCP1 gene. The isoform 2 transcript continues from the exon 4 end into the adjacent intron, where it terminates shortly at an alternative polyadenylation signal, giving rise to a truncated transcript (Perry et al., 2007). The isoform 2 encodes a truncated, secreted protein of 343 amino acids, that contains the N-terminal part of the extracellular domain (and one CUB domain) of CDCP1 and lacks the transmembrane and intracellular modules. Currently, most studies have been focused on the more prominently expressed isoform 1. The function and expression of isoform 2 remains poorly understood.
Pseudogene No pseudogenes, related to CDCP1 are present in the human genome.

Protein

Note The full-length CDCP1 protein consists of 836 amino acids. The SDS PAGE migration of CDCP1 protein is approximately 140 kDa, which differs from its calculated molecular weight (approximately 90 kDa) due to extensive glycosylation (Bhatt et al., 2005). CDCP1 is cleaved by serine proteases at the extracellular domain next to Arg368 to generate a truncated molecule of 80 kDa size (Bhatt et al., 2005) (in some cases it is referred as 70kDa). Different cell lines express different amounts of p140 and p80, depending on the activity of endogenous serine proteases (Spassov et al., 2012). In vivo, CDCP1 is not cleaved during normal physiological circumstances, but its cleavage can be induced during tumorigenesis or tissue injury. (Spassov et al., 2011; Spassov et al., 2013).
 
  CDCP1 contains a signal peptide and a transmembrane region for proper membrane localization. The larger extracellular domain contains two or three CUB domains. The triangles indicate the naturally occurring cleavage sites after the signal peptide and at Arg368 of the extracellular domain. Abbreviations indicate the signal peptide (SP), CUB domains, transmembrane region (TM), proline-rich region (PRR). The intracellular domain contains 5 tyrosine residues (indicated by Y) all of which can be specifically phosphorylated by Src family kinases.
Description The full-length CDCP1 protein is a type I transmembrane protein. The proper membrane localization is ensured by the presence of a signal peptide and a transmembrane domain (Bhatt et al., 2005). The extracellular region is large and it is reported to contain two or three CUB domains. This difference arises because one of the Cub domains has a very weak degree of homology and may not be recognized readily as a Cub domain depending on the software used. The CUB (Complement protein components C1, Urchin embryonic growth factor and Bone morphogenic protein 1) domains are characterized by immunoglobulin-like folds and are involved in protein-protein interactions and are found in functionally diverse, mostly developmentally regulated proteins and in peptidases. The intracellular domain of CDCP1 contains five tyrosine residues - Y707, Y734, Y743, Y762 and Y806. Phosphorylation of CDCP1 is exclusively mediated by Src kinases (Bhatt et al., 2005).
Expression CDCP1 is predominantly expressed in epithelial tissues and its expression is not detectable in fibroblasts and other mesenchymal cells (Spassov et al., 2009). CDCP1 also has been reported to be expressed in hematopoietic progenitor cells but not in mature blood cell types (Bühring et al., 2004).
Localisation CDCP1 is a transmembrane protein and is located on the cell membrane.
Function CDCP1, when phosphorylated, functions to inhibit integrin signaling, disrupt focal adhesions and oppose cell adhesion (Spassov et al., 2011). Phosphorylation of CDCP1 depends on the adherence state of the cells (Spassov et al., 2009). The loss of anchorage or cellular detachment is associated with the phosphorylation of CDCP1 as well as the concomitant dephosphorylation of focal adhesion proteins, consistent with the dismantling of focal adhesions (Spassov et al., 2011). Contrary, during cellular attachment CDCP1 is dephosphorylated, allowing the phosphorylation of focal adhesion proteins. Knockdown of CDCP1 leads to increased adhesiveness and experimentally induced over-expression and phosphorylation of CDCP1 decreases cell adhesion and leads to cell rounding and a detached phenotype (Spassov et al., 2011). CDCP1 regulates cellular migration and both loss of function and gain of functions of CDCP1 can lead to inhibition of migration (Spassov et al., 2011). The knockdown of CDCP1 leads to permanent cell attachment to substratum, while its excessive phosphorylation inhibits cell spreading and cell motility. The anti-adhesion and anti-migratory functions of CDCP1 are mediated through negative regulation on integrin receptors (Spassov et al., 2011). When phosphorylated by Src kinases, CDCP1 appears in complexes containing β1 integrin, interfering with integrin clustering and preventing the mechanical and signaling events that link the intracellular cytoskeleton with the extracellular matrix. This is mediated through the inhibition of integrin clustering without affecting integrin affinity state or ligand binding activity (Spassov et al., 2011).
Homology The human genome does not contain other genes related to CDCP1. The degree of homology within the CUB domains of other proteins is low (maximum 20% identity). More importantly other CUB domain containing proteins do not contain the intracellular module that is regulated and phosphorylated by Src kinases. This indicates that there is no other related gene in the human genome that may play a redundant role with CDCP1. CDCP1 homologs are present only in the vertebrate species, including zebra fish, Xenopus, chicken and mammals. CDCP1 is not present in invertebrates and lower organisms.

Mutations

Note CDCP1 is localized on chromosomal region (3p21.31), which is very frequently deleted in human cancers (Ji et al., 2005). LOH of CDCP1 is frequent (90-100%) in lung cancers and has been observed in breast cancers and other cancer types.
Germinal Germinal mutations associated with disease have not been described yet. Several polymorphic sites are described in the gene databases. The role of these polymorphic sites is currently unknown.
Somatic Somatic mutations in cancer are infrequent. According to COSMIC database (http://cancer.sanger.ac.uk) currently (June 2013) 38 somatic cancer mutations have been identified from 7080 tumor samples (0.5%). Some cancer types show somewhat elevated mutational frequency; for instance 2.4% in melanoma and 1.4 % in colon cancer. It is unclear at this moment if these mutations have functional significance or represent passenger mutations.

Implicated in

Note
  
Entity Tumorigenesis
Note Expression and phosphorylation in tumors
The expression of CDCP1 relative to the normal epithelium is reduced or lost in some tumors, particularly in breast, colon, prostate and lung cancers (Wong et al., 2009; Spassov et al., 2012). This is due to loss of heterozygosity in CDCP1 genomic region and/or promoter methylation (Spassov et al., 2012). CDCP1 is widely and abundantly expressed in human epithelial tissues, but its phosphorylation is not detectable in normally anchored epithelial layers (Spassov et al., 2009). However, phosphorylation of CDCP1 is seen in many epithelial tumors from all stages including early stage carcinomas, invasive, and metastatic tumors (Wong et al., 2009). The phosphorylation of CDCP1 in tumors suggests that they may exist at an abnormal or deficient state of anchorage in vivo (Spassov et al., 2011). This may be due to abnormalities in the composition of the surrounding matrix, defective assembly of adhesion complexes, or defective signaling through the integrin adhesion complex. Specifically, this may be due to the absence of a continuous basal lamina which typically underlies the basal surface of epithelial cells in the normal epithelium but is highly abnormal or missing in epithelial tumors.
Animal model
Mice lacking CDCP1 do not exhibit gross morphologic, reproductive or behavioral abnormalities compared with wild-type mice, and histologic examination of multiple organ systems found no significant pathology and no observed histologic differences (Spassov et al., 2013). Mammary tumors driven by the PyMT oncogene and skin tumors driven by activation of Hedgehog pathway developed with accelerated kinetics in CDCP1 null mice, establishing a tumor suppressing function for this gene during cancer initiation and evolution (Spassov et al., 2013). Mechanistic investigations in mammary tumor cell lines derived from CDCP1-deficient mice revealed a de-repression of integrin signaling and an enhancement of integrin-growth factor receptor cross-talk; hence increased growth factor signaling and cell proliferation of CDCP1 null cancer cells (Spassov et al., 2013).
Metastasis
The role of CDCP1 in cellular migration may suggest a potential role of this gene in cancer metastasis. However, this role may be a complex one, considering that both loss of function and gain of function of CDCP1 inhibit migratory capacity of the cells. Inducible expression and phosphorylation of CDCP1 in breast cancer MCF7 cell line decreased the number of lymph node metastasis after orthotopic mammary fat pad implantation (Spassov et al., 2012). Similarly, the inducible expression of CDCP1 in v-src transformed NIH3T3 cells significantly decreased the lung colonization capacity of the cells after tail vein inoculation (Spassov et al., 2012). Knockdown of CDCP1 have also been reported to decrease experimental metastasis of lung and melanoma cell lines (Uekita et al., 2007; Liu et al., 2011). Future work is required to elucidate the functions of CDCP1 in cancer metastasis and whether there will be clinical benefits of targeting this gene. Several efforts have been made to target CDCP1 with monoclonal antibody that recognizes the extracellular domain of the protein. Such antibodies induce the phosphorylation of CDCP1 and have been shown to suppress experimental metastasis in preclinical models (Siva at al., 2008; Casar et al., 2012). It is unclear if this is due to effects on CDCP1 function or if it is mediated through immunological mechanisms.
Hybrid/Mutated Gene No hybrid genes, containing CDCP1 are known.
Abnormal Protein No fusions with CDCP1 have been reported.
Oncogenesis CDCP1 null mice show accelerated oncogenesis in genetically modified experimental models of skin and breast cancers.
  

Bibliography

Adhesion signaling by a novel mitotic substrate of src kinases.
Bhatt AS, Erdjument-Bromage H, Tempst P, Craik CS, Moasser MM.
Oncogene. 2005 Aug 11;24(34):5333-43.
PMID 16007225
 
CDCP1 identifies a broad spectrum of normal and malignant stem/progenitor cell subsets of hematopoietic and nonhematopoietic origin.
Buhring HJ, Kuci S, Conze T, Rathke G, Bartolovic' K, Grunebach F, Scherl-Mostageer M, Brummendorf TH, Schweifer N, Lammers R.
Stem Cells. 2004;22(3):334-43.
PMID 15153610
 
Blocking of CDCP1 cleavage in vivo prevents Akt-dependent survival and inhibits metastatic colonization through PARP1-mediated apoptosis of cancer cells.
Casar B, He Y, Iconomou M, Hooper JD, Quigley JP, Deryugina EI.
Oncogene. 2012 Aug 30;31(35):3924-38. doi: 10.1038/onc.2011.555. Epub 2011 Dec 19.
PMID 22179830
 
3p21.3 tumor suppressor cluster: prospects for translational applications.
Ji L, Minna JD, Roth JA.
Future Oncol. 2005 Feb;1(1):79-92. (REVIEW)
PMID 16555978
 
CUB-domain-containing protein 1 (CDCP1) activates Src to promote melanoma metastasis.
Liu H, Ong SE, Badu-Nkansah K, Schindler J, White FM, Hynes RO.
Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1379-84. doi: 10.1073/pnas.1017228108. Epub 2011 Jan 10.
PMID 21220330
 
Expression of the CUB domain containing protein 1 (CDCP1) gene in colorectal tumour cells.
Perry SE, Robinson P, Melcher A, Quirke P, Buhring HJ, Cook GP, Blair GE.
FEBS Lett. 2007 Mar 20;581(6):1137-42. Epub 2007 Feb 20.
PMID 17335815
 
Identification of a novel gene, CDCP1, overexpressed in human colorectal cancer.
Scherl-Mostageer M, Sommergruber W, Abseher R, Hauptmann R, Ambros P, Schweifer N.
Oncogene. 2001 Jul 19;20(32):4402-8.
PMID 11466621
 
Targeting CUB domain-containing protein 1 with a monoclonal antibody inhibits metastasis in a prostate cancer model.
Siva AC, Wild MA, Kirkland RE, Nolan MJ, Lin B, Maruyama T, Yantiri-Wernimont F, Frederickson S, Bowdish KS, Xin H.
Cancer Res. 2008 May 15;68(10):3759-66. doi: 10.1158/0008-5472.CAN-07-1657.
PMID 18483259
 
Trask loss enhances tumorigenic growth by liberating integrin signaling and growth factor receptor cross-talk in unanchored cells.
Spassov DS, Wong CH, Wong SY, Reiter JF, Moasser MM.
Cancer Res. 2013 Feb 1;73(3):1168-79. doi: 10.1158/0008-5472.CAN-12-2496. Epub 2012 Dec 12.
PMID 23243018
 
CUB domain-containing protein 1 is a novel regulator of anoikis resistance in lung adenocarcinoma.
Uekita T, Jia L, Narisawa-Saito M, Yokota J, Kiyono T, Sakai R.
Mol Cell Biol. 2007 Nov;27(21):7649-60. Epub 2007 Sep 4.
PMID 17785447
 
Phosphorylation of the SRC epithelial substrate Trask is tightly regulated in normal epithelia but widespread in many human epithelial cancers.
Wong CH, Baehner FL, Spassov DS, Ahuja D, Wang D, Hann B, Blair J, Shokat K, Welm AL, Moasser MM.
Clin Cancer Res. 2009 Apr 1;15(7):2311-22. doi: 10.1158/1078-0432.CCR-08-2533. Epub 2009 Mar 24.
PMID 19318475
 

Citation

This paper should be referenced as such :
Moasser, M ; Spassov, D
CDCP1 (CUB domain containing protein 1)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(1):1-4.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CDCP1ID40016ch3p21.html


External links

Nomenclature
HGNC (Hugo)CDCP1   24357
Cards
AtlasCDCP1ID40016ch3p21
Entrez_Gene (NCBI)CDCP1  64866  CUB domain containing protein 1
AliasesCD318; SIMA135; TRASK
GeneCards (Weizmann)CDCP1
Ensembl hg19 (Hinxton)ENSG00000163814 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000163814 [Gene_View]  chr3:45082274-45146422 [Contig_View]  CDCP1 [Vega]
ICGC DataPortalENSG00000163814
TCGA cBioPortalCDCP1
AceView (NCBI)CDCP1
Genatlas (Paris)CDCP1
WikiGenes64866
SOURCE (Princeton)CDCP1
Genetics Home Reference (NIH)CDCP1
Genomic and cartography
GoldenPath hg38 (UCSC)CDCP1  -     chr3:45082274-45146422 -  3p21.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CDCP1  -     3p21.31   [Description]    (hg19-Feb_2009)
EnsemblCDCP1 - 3p21.31 [CytoView hg19]  CDCP1 - 3p21.31 [CytoView hg38]
Mapping of homologs : NCBICDCP1 [Mapview hg19]  CDCP1 [Mapview hg38]
OMIM611735   
Gene and transcription
Genbank (Entrez)AF468010 AK023834 AK026187 AK026329 AK026622
RefSeq transcript (Entrez)NM_022842 NM_178181
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CDCP1
Cluster EST : UnigeneHs.476093 [ NCBI ]
CGAP (NCI)Hs.476093
Alternative Splicing GalleryENSG00000163814
Gene ExpressionCDCP1 [ NCBI-GEO ]   CDCP1 [ EBI - ARRAY_EXPRESS ]   CDCP1 [ SEEK ]   CDCP1 [ MEM ]
Gene Expression Viewer (FireBrowse)CDCP1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)64866
GTEX Portal (Tissue expression)CDCP1
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9H5V8   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9H5V8  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9H5V8
Splice isoforms : SwissVarQ9H5V8
PhosPhoSitePlusQ9H5V8
Domains : Interpro (EBI)CUB_dom   
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)CDCP1
DMDM Disease mutations64866
Blocks (Seattle)CDCP1
SuperfamilyQ9H5V8
Human Protein AtlasENSG00000163814
Peptide AtlasQ9H5V8
HPRD16696
IPIIPI00290039   IPI00736241   IPI00235622   
Protein Interaction databases
DIP (DOE-UCLA)Q9H5V8
IntAct (EBI)Q9H5V8
FunCoupENSG00000163814
BioGRIDCDCP1
STRING (EMBL)CDCP1
ZODIACCDCP1
Ontologies - Pathways
QuickGOQ9H5V8
Ontology : AmiGOprotein binding  extracellular region  plasma membrane  integral component of membrane  
Ontology : EGO-EBIprotein binding  extracellular region  plasma membrane  integral component of membrane  
NDEx NetworkCDCP1
Atlas of Cancer Signalling NetworkCDCP1
Wikipedia pathwaysCDCP1
Orthology - Evolution
OrthoDB64866
GeneTree (enSembl)ENSG00000163814
Phylogenetic Trees/Animal Genes : TreeFamCDCP1
HOVERGENQ9H5V8
HOGENOMQ9H5V8
Homologs : HomoloGeneCDCP1
Homology/Alignments : Family Browser (UCSC)CDCP1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCDCP1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CDCP1
dbVarCDCP1
ClinVarCDCP1
1000_GenomesCDCP1 
Exome Variant ServerCDCP1
ExAC (Exome Aggregation Consortium)CDCP1 (select the gene name)
Genetic variants : HAPMAP64866
Genomic Variants (DGV)CDCP1 [DGVbeta]
DECIPHERCDCP1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCDCP1 
Mutations
ICGC Data PortalCDCP1 
TCGA Data PortalCDCP1 
Broad Tumor PortalCDCP1
OASIS PortalCDCP1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCDCP1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCDCP1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CDCP1
DgiDB (Drug Gene Interaction Database)CDCP1
DoCM (Curated mutations)CDCP1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CDCP1 (select a term)
intoGenCDCP1
NCG5 (London)CDCP1
Cancer3DCDCP1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM611735   
Orphanet
MedgenCDCP1
Genetic Testing Registry CDCP1
NextProtQ9H5V8 [Medical]
TSGene64866
GENETestsCDCP1
Target ValidationCDCP1
Huge Navigator CDCP1 [HugePedia]
snp3D : Map Gene to Disease64866
BioCentury BCIQCDCP1
ClinGenCDCP1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD64866
Chemical/Pharm GKB GenePA142672140
Clinical trialCDCP1
Miscellaneous
canSAR (ICR)CDCP1 (select the gene name)
Probes
Litterature
PubMed68 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCDCP1
EVEXCDCP1
GoPubMedCDCP1
iHOPCDCP1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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