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CEMIP (cell migration inducing protein, hyaluronan binding )

Written2013-10Nikki Ann Evensen, Cem Kuscu, Jian Cao
Stony Brook University, Stony Brook, New York, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesKIAA1199
KIAA1199
cell migration inducing protein, hyaluronan binding
Alias_symbol (synonym)IR2155535
TMEM2L
HYBID
Other alias
HGNC (Hugo) CEMIP
LocusID (NCBI) 57214
Atlas_Id 51053
Location 15q25.1  [Link to chromosome band 15q25]
Location_base_pair Starts at 81071684 and ends at 81244003 bp from pter ( according to hg19-Feb_2009)  [Mapping CEMIP.png]
Fusion genes
(updated 2016)
CEMIP (15q25.1) / ABHD17C (15q25.1)CEMIP (15q25.1) / CEMIP (15q25.1)DOPEY1 (6q14.1) / CEMIP (15q25.1)
MALAT1 (11q13.1) / CEMIP (15q25.1)PIGP (21q22.13) / CEMIP (15q25.1)TIMP2 (17q25.3) / CEMIP (15q25.1)
Note Reported in the Human Unidentified Gene-Encoded Large Proteins (HUGE) database as KIAA1199.

DNA/RNA

 
Description The human KIAA1199 transcript spans 7080 base pairs on chromosome 15 in the region 15q25.1. It contains 29 exons, 28 of which are coding, and 28 introns. The transcriptional start site is within the second exon. There is a canonical TATA-box present in the KIAA1199 promoter region at -31 to -27 base pairs, as well as a GC-box at -248 to -243 base pairs. However, this GC-box was not found to be required for transcriptional activation of KIAA1199, nor was there any methylation of the cytosines found within this region, which is often an important feature of GC-boxes. KIAA1199 also contains a CpG island within the first intron (+525 50 +1025). The methylation status of this CpG island was found to effect the expression level of KIAA1199, with high levels of DNA methylation found in non-aggressive, low expressing, cancer cell lines (Kuscu et al., 2012).
Transcription An AP-1 binding site, located between -48 and -45 within the KIAA1199 promoter, was found to be important for KIAA1199 promoter activity. AP-1 was found to directly bind to this region in order to activate transcription of KIAA1199. AP-1 transcription factors have been associated with increased promoter activity of genes associated with cancer. Additionally, among four potential NF-κB binding sites, the site furthest from the transcriptional start site (-1345 to -1333) was found to play a role in KIAA1199 promoter activation. NF-κB was found to directly bind to this site to increase transcription of KIAA1199 (Kuscu et al., 2012).

Protein

Description The KIAA1199 open reading frame consists of 4083 base pairs, which encodes a protein 1361 amino acids in length. It has a predicted molecular weight of approximately 163 kDa. The KIAA1199 protein has a G8 domain between a.a. 44-166, which is a novel domain that contains eight conserved glycines and consists of five β-strand pairs (He et al., 2006). Several disease related proteins contain this domain, including polyductin protein (PKHD1) and transmembrane protein 2 (TMEM2), although the exact function of the G8 motif remains unclear (He et al., 2006). A GG domain, characterized by seven β-strands and two α-helices, can also be found within the KIAA1199 protein (Guo et al., 2006). This novel domain also has no known function. KIAA1199 is also predicted to have a cleavable signal peptide at its NH2-terminus (Sabates-Bellver et al., 2007). KIAA1199 has been demonstrated to be N-linked glycosylated (Tiwari et al., 2013).
Expression Northern blot analysis of normal human tissues revealed expression of KIAA1199 mRNA in various tissues, with the highest levels found in the brain, placenta, lung, and testis (Michishita et al., 2006). KIAA1199 is also expressed in various cell types found in the inner ear (Abe et al., 2003; Usami et al., 2008), and in dermal fibroblasts of the skin (Yoshida et al., 2013). Increased levels of KIAA1199 have also been demonstrated in numerous cancer tissues compared to normal tissues, including colorectal adenomas (Sabates-Bellver et al., 2007).
Localisation Cytoplasmic and nuclear staining for KIAA1199 has been observed in gastric and colon cancer tissue samples (Sabates-Bellver et al., 2007; Matsuzaki et al., 2009; Birkenkamp-Demtroder et al., 2011). More detailed subcellular localization revealed expression of exogenous and endogenous KIAA1199 within the endoplasmic reticulum (ER) of various cell types (Evensen et al., 2013; Tiwari et al., 2013). KIAA1199 was found to interact with the ER chaperone binding immunoglobulin protein (BiP)/glucose-regulated protein (GRP-78), which further supports the ER localization of KIAA1199 (Evensen et al., 2013). Secretion of KIAA1199 has also been demonstrated for certain cell types (Tiwari et al., 2013).
Function KIAA1199 plays a key role in cancer progression via increasing cancer cell migration and invasion, which are necessary steps for cancer metastasis. Expression of KIAA1199 in non-aggressive cancer cell lines leads to an epithelial-to-mesenchymal transition along with increased migratory capabilites. Furthermore, knockdown of KIAA1199 leads to a loss of mesenchymal characteristics with decreased invasive and migratory abilities, as well as reduced metastastic potential (Evensen et al., 2013).
A role for KIAA1199 in maintaining ion homeostasis, and more specifically calcium signaling, has also been suggested (Abe et al., 2003; Tiwari et al., 2013). KIAA1199-mediated migration was found to involve elevated cytosolic calcium levels followed by protein kinase C alpha (PKCα) translocation/activation. This change in cytosolic calcium is due to increased release of calcium from the ER via an unknown mechanism induced by KIAA1199 (Evensen et al., 2013). Additional studies revealed an interaction with KIAA1199 and inositol 1,4,5-triphosphate receptor 3 (ITPR3) which is a ligand-gated ion channel located on the ER membrane that is known to mediate the release of calcium from the ER (Tiwari et al., 2013).
KIAA1199 is thought to be a target of the Wnt signaling pathway and a potential player in the progression of colorectal adenomatous (Sabates-Bellver et al., 2007; Tiwari et al., 2013). Additionally, silencing of KIAA1199 was shown to alter the expression of genes known to be involved in the Wnt/β-catenin pathway and decrease cell proliferation (Birkenkamp-Demtroder et al., 2011).
In human skin fibroblasts, KIAA1199 expression was found to cause increased degradation of hyaluronan (HA), which is a glycosaminoglycan found in the extracellular matrix surrounding tissues. It acts as a structural component and can affect cell signaling and cellular behavior, including angiogenesis and cell migration (Yoshida et al., 2013).
Homology The KIAA1199 gene product shares 38% identity (63% similarity) with transmembrane protein 2 (TMEM2). A small region within the KIAA1199 gene product (aa 55-155) also shares 38% identity (57% similarity) with polyductin protein (PKHD1) (Abe et al., 2003). However, none of these homologies revealed any functional information.

Mutations

Somatic Nine DNA variants of the KIAA1199 gene were identified, six of which were missense (R187C, R187H, H783R, H783Y, V1109I, and P1169A) and three of which were synonymous substitutions (L532L, P619P, D800D). R187C, R187H, H783Y, and V1109I were found only in families with nonsyndromic hearing loss, suggesting a potential role for these specific mutations in this disease state (Abe et al., 2003).

Implicated in

Note
  
Entity Gastric and colorectal cancers
Prognosis Numerous studies have implicated KIAA1199 expression with cancer progression. Gastric cancer patients with low expression of KIAA1199 were found to have significantly better overall 5-year survival rates as compared to those expressing higher levels. Furthermore, lymph node metastasis, distant metastasis, and peritoneal dissemination were more often observed in the patients with higher levels of KIAA1199 (Matsuzaki et al., 2009).
Additionally, there is evidence to suggest that KIAA1199 could potentially be used as a biomarker for cancer. Higher levels of KIAA1199 transcripts were found in the serum of patients with adenoma and colorectal cancer as compared to neoplasia free controls (LaPointe et al., 2012). KIAA1199 was also found to be upregulated in cancerous tissues from gastric adenocarcinoma patients, further supporting the idea of using KIAA1199 for diagnostics, early detection, or as a predictor of cancer progression (Chivu Economescu et al., 2010).
  
  
Entity Nonsyndromic hearing loss
Prognosis Several mutations within KIAA1199 were found in patients with nonsyndromic hearing loss but not in control subjects. Based on the expression pattern of KIAA1199 in the cells of the inner ear, it is thought that it could play a role in normal auditory development with these particular mutations having a negative impact (Abe et al., 2003).
  

Bibliography

Mutations in the gene encoding KIAA1199 protein, an inner-ear protein expressed in Deiters' cells and the fibrocytes, as the cause of nonsyndromic hearing loss.
Abe S, Usami S, Nakamura Y.
J Hum Genet. 2003;48(11):564-70. Epub 2003 Oct 24.
PMID 14577002
 
Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells.
Birkenkamp-Demtroder K, Maghnouj A, Mansilla F, Thorsen K, Andersen CL, Oster B, Hahn S, Orntoft TF.
Br J Cancer. 2011 Aug 9;105(4):552-61. doi: 10.1038/bjc.2011.268. Epub 2011 Jul 19.
PMID 21772334
 
Identification of potential biomarkers for early and advanced gastric adenocarcinoma detection.
Chivu Economescu M, Necula LG, Dragu D, Badea L, Dima SO, Tudor S, Nastase A, Popescu I, Diaconu CC.
Hepatogastroenterology. 2010 Nov-Dec;57(104):1453-64.
PMID 21443102
 
Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration.
Evensen NA, Kuscu C, Nguyen HL, Zarrabi K, Dufour A, Kadam P, Hu YJ, Pulkoski-Gross A, Bahou WF, Zucker S, Cao J.
J Natl Cancer Inst. 2013 Sep 18;105(18):1402-16. doi: 10.1093/jnci/djt224. Epub 2013 Aug 29.
PMID 23990668
 
GG: a domain involved in phage LTF apparatus and implicated in human MEB and non-syndromic hearing loss diseases.
Guo J, Cheng H, Zhao S, Yu L.
FEBS Lett. 2006 Jan 23;580(2):581-4. Epub 2006 Jan 3.
PMID 16406369
 
G8: a novel domain associated with polycystic kidney disease and non-syndromic hearing loss.
He QY, Liu XH, Li Q, Studholme DJ, Li XW, Liang SP.
Bioinformatics. 2006 Sep 15;22(18):2189-91. Epub 2006 Apr 21.
PMID 16632497
 
Transcriptional and epigenetic regulation of KIAA1199 gene expression in human breast cancer.
Kuscu C, Evensen N, Kim D, Hu YJ, Zucker S, Cao J.
PLoS One. 2012;7(9):e44661. doi: 10.1371/journal.pone.0044661. Epub 2012 Sep 6.
PMID 22970280
 
Discovery and validation of molecular biomarkers for colorectal adenomas and cancer with application to blood testing.
LaPointe LC, Pedersen SK, Dunne R, Brown GS, Pimlott L, Gaur S, McEvoy A, Thomas M, Wattchow D, Molloy PL, Young GP.
PLoS One. 2012;7(1):e29059. doi: 10.1371/journal.pone.0029059. Epub 2012 Jan 19.
PMID 22276102
 
Clinicopathologic significance of KIAA1199 overexpression in human gastric cancer.
Matsuzaki S, Tanaka F, Mimori K, Tahara K, Inoue H, Mori M.
Ann Surg Oncol. 2009 Jul;16(7):2042-51. doi: 10.1245/s10434-009-0469-6. Epub 2009 May 12.
PMID 19434458
 
Upregulation of the KIAA1199 gene is associated with cellular mortality.
Michishita E, Garces G, Barrett JC, Horikawa I.
Cancer Lett. 2006 Jul 28;239(1):71-7. Epub 2005 Sep 12.
PMID 16157444
 
Transcriptome profile of human colorectal adenomas.
Sabates-Bellver J, Van der Flier LG, de Palo M, Cattaneo E, Maake C, Rehrauer H, Laczko E, Kurowski MA, Bujnicki JM, Menigatti M, Luz J, Ranalli TV, Gomes V, Pastorelli A, Faggiani R, Anti M, Jiricny J, Clevers H, Marra G.
Mol Cancer Res. 2007 Dec;5(12):1263-75. doi: 10.1158/1541-7786.MCR-07-0267.
PMID 18171984
 
Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors.
Tiwari A, Schneider M, Fiorino A, Haider R, Okoniewski MJ, Roschitzki B, Uzozie A, Menigatti M, Jiricny J, Marra G.
PLoS One. 2013 Jul 23;8(7):e69473. doi: 10.1371/journal.pone.0069473. Print 2013.
PMID 23936024
 
The localization of proteins encoded by CRYM, KIAA1199, UBA52, COL9A3, and COL9A1, genes highly expressed in the cochlea.
Usami S, Takumi Y, Suzuki N, Oguchi T, Oshima A, Suzuki H, Kitoh R, Abe S, Sasaki A, Matsubara A.
Neuroscience. 2008 Jun 12;154(1):22-8. doi: 10.1016/j.neuroscience.2008.03.018. Epub 2008 Mar 19.
PMID 18448257
 
KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.
Yoshida H, Nagaoka A, Kusaka-Kikushima A, Tobiishi M, Kawabata K, Sayo T, Sakai S, Sugiyama Y, Enomoto H, Okada Y, Inoue S.
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5612-7. doi: 10.1073/pnas.1215432110. Epub 2013 Mar 18.
PMID 23509262
 

Citation

This paper should be referenced as such :
Evensen, NA ; Kuscu, C ; Cao, J
KIAA1199 (KIAA1199)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(5):324-326.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/KIAA1199ID51053ch15q25.html


External links

Nomenclature
HGNC (Hugo)CEMIP   29213
Cards
AtlasKIAA1199ID51053ch15q25
Entrez_Gene (NCBI)CEMIP  57214  cell migration inducing protein, hyaluronan binding
AliasesCCSP1; KIAA1199; TMEM2L
GeneCards (Weizmann)CEMIP
Ensembl hg19 (Hinxton)ENSG00000103888 [Gene_View]  chr15:81071684-81244003 [Contig_View]  CEMIP [Vega]
Ensembl hg38 (Hinxton)ENSG00000103888 [Gene_View]  chr15:81071684-81244003 [Contig_View]  CEMIP [Vega]
ICGC DataPortalENSG00000103888
TCGA cBioPortalCEMIP
AceView (NCBI)CEMIP
Genatlas (Paris)CEMIP
WikiGenes57214
SOURCE (Princeton)CEMIP
Genetics Home Reference (NIH)CEMIP
Genomic and cartography
GoldenPath hg19 (UCSC)CEMIP  -     chr15:81071684-81244003 +  15q25.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)CEMIP  -     15q25.1   [Description]    (hg38-Dec_2013)
EnsemblCEMIP - 15q25.1 [CytoView hg19]  CEMIP - 15q25.1 [CytoView hg38]
Mapping of homologs : NCBICEMIP [Mapview hg19]  CEMIP [Mapview hg38]
OMIM608366   
Gene and transcription
Genbank (Entrez)AB033025 AB103330 AK000465 AK026540 AK027058
RefSeq transcript (Entrez)NM_001293298 NM_001293304 NM_018689
RefSeq genomic (Entrez)NC_000015 NC_018926 NT_010194 NW_004929398
Consensus coding sequences : CCDS (NCBI)CEMIP
Cluster EST : UnigeneHs.459088 [ NCBI ]
CGAP (NCI)Hs.459088
Alternative Splicing GalleryENSG00000103888
Gene ExpressionCEMIP [ NCBI-GEO ]   CEMIP [ EBI - ARRAY_EXPRESS ]   CEMIP [ SEEK ]   CEMIP [ MEM ]
Gene Expression Viewer (FireBrowse)CEMIP [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)57214
GTEX Portal (Tissue expression)CEMIP
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8WUJ3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8WUJ3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8WUJ3
Splice isoforms : SwissVarQ8WUJ3
Catalytic activity : Enzyme3.2.1.35 [ Enzyme-Expasy ]   3.2.1.353.2.1.35 [ IntEnz-EBI ]   3.2.1.35 [ BRENDA ]   3.2.1.35 [ KEGG ]   
PhosPhoSitePlusQ8WUJ3
Domaine pattern : Prosite (Expaxy)G8 (PS51484)   
Domains : Interpro (EBI)G8_domain    Pectin_lyas_fold    Pectin_lyase_fold/virulence    WxxW_domain   
Domain families : Pfam (Sanger)G8 (PF10162)    Mucin2_WxxW (PF13330)   
Domain families : Pfam (NCBI)pfam10162    pfam13330   
Conserved Domain (NCBI)CEMIP
DMDM Disease mutations57214
Blocks (Seattle)CEMIP
SuperfamilyQ8WUJ3
Human Protein AtlasENSG00000103888
Peptide AtlasQ8WUJ3
HPRD10519
IPIIPI00376689   IPI00291170   IPI00977929   
Protein Interaction databases
DIP (DOE-UCLA)Q8WUJ3
IntAct (EBI)Q8WUJ3
FunCoupENSG00000103888
BioGRIDCEMIP
STRING (EMBL)CEMIP
ZODIACCEMIP
Ontologies - Pathways
QuickGOQ8WUJ3
Ontology : AmiGOhyalurononglucosaminidase activity  hyalurononglucosaminidase activity  protein binding  hyaluronic acid binding  extracellular region  nucleus  cytoplasm  cytoplasm  endoplasmic reticulum  plasma membrane  coated pit  sensory perception of sound  positive regulation of peptidyl-threonine phosphorylation  hyaluronan biosynthetic process  hyaluronan catabolic process  positive regulation of cell migration  clathrin-coated vesicle membrane  clathrin heavy chain binding  ER retention sequence binding  positive regulation of release of sequestered calcium ion into cytosol  positive regulation of protein targeting to membrane  positive regulation of protein kinase C activity  
Ontology : EGO-EBIhyalurononglucosaminidase activity  hyalurononglucosaminidase activity  protein binding  hyaluronic acid binding  extracellular region  nucleus  cytoplasm  cytoplasm  endoplasmic reticulum  plasma membrane  coated pit  sensory perception of sound  positive regulation of peptidyl-threonine phosphorylation  hyaluronan biosynthetic process  hyaluronan catabolic process  positive regulation of cell migration  clathrin-coated vesicle membrane  clathrin heavy chain binding  ER retention sequence binding  positive regulation of release of sequestered calcium ion into cytosol  positive regulation of protein targeting to membrane  positive regulation of protein kinase C activity  
REACTOMEQ8WUJ3 [protein]
REACTOME Pathways2142850 [pathway]   
NDEx NetworkCEMIP
Atlas of Cancer Signalling NetworkCEMIP
Wikipedia pathwaysCEMIP
Orthology - Evolution
OrthoDB57214
GeneTree (enSembl)ENSG00000103888
Phylogenetic Trees/Animal Genes : TreeFamCEMIP
HOVERGENQ8WUJ3
HOGENOMQ8WUJ3
Homologs : HomoloGeneCEMIP
Homology/Alignments : Family Browser (UCSC)CEMIP
Gene fusions - Rearrangements
Fusion : MitelmanCEMIP/ABHD17C [15q25.1/15q25.1]  
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCEMIP [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CEMIP
dbVarCEMIP
ClinVarCEMIP
1000_GenomesCEMIP 
Exome Variant ServerCEMIP
ExAC (Exome Aggregation Consortium)CEMIP (select the gene name)
Genetic variants : HAPMAP57214
Genomic Variants (DGV)CEMIP [DGVbeta]
DECIPHER (Syndromes)15:81071684-81244003  ENSG00000103888
CONAN: Copy Number AnalysisCEMIP 
Mutations
ICGC Data PortalCEMIP 
TCGA Data PortalCEMIP 
Broad Tumor PortalCEMIP
OASIS PortalCEMIP [ Somatic mutations - Copy number]
Mutations and Diseases : HGMDCEMIP
BioMutasearch CEMIP
DgiDB (Drug Gene Interaction Database)CEMIP
DoCM (Curated mutations)CEMIP (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CEMIP (select a term)
intoGenCEMIP
NCG5 (London)CEMIP
Cancer3DCEMIP(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM608366   
Orphanet
MedgenCEMIP
Genetic Testing Registry CEMIP
NextProtQ8WUJ3 [Medical]
TSGene57214
GENETestsCEMIP
Huge Navigator CEMIP [HugePedia]
snp3D : Map Gene to Disease57214
BioCentury BCIQCEMIP
ClinGenCEMIP
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD57214
Chemical/Pharm GKB GenePA134967531
Clinical trialCEMIP
Miscellaneous
canSAR (ICR)CEMIP (select the gene name)
Probes
Litterature
PubMed25 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCEMIP
EVEXCEMIP
GoPubMedCEMIP
iHOPCEMIP
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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