| 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 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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