KIAA1199, the source of deafness revealed ?
During his medical studies at the university of Pavia, Alfonso developed a pronounced taste for surgery and microscopy. Eager to better understand the earing process, Alfonso Corti planned to dissect several cochleas of man and different animals under the supervision of the famous German anatomist Albert Kölliker.
In March 1850, Corti began researching the spiral organ and the auditory nerve, while observing the movement of the eyelashes of the intestine in frogs, and finally published his results in 1851 (1). The term "Cortie's organ", as a name for the receiving organ of hearing, was then proposed and introduced by Kölliker. In 1860, based on Corti’s work, Otto Deiters found phalangeal cells located in the inner cells in the Cortie’s organ, supporting the hair cell in a cup-shaped depression (2). The anatomia of cochlea was complete.
A century and a half later, Abe et al. decided to understand the hearing loss at a molecular level and identified 52 genes expressed in the human inner ear and related to nonsyndromic deafness. Screening these genes, one after the other in the HUGE database (3), they finally identified three point mutations in KIAA1199 protein gene (KIAA1199), expressed in Deiters’ cells (4).
KIAA1199 is located on chromosome band 15q25.1 and encodes a 153 KDa protein containing three domains and an N-terminal signal peptide. In analyzing the protein sequence of gp35, Guo et al. found a novel protein domain present in not only gp35 and but also a variety of eukaryotic proteins, including FAM3 superfamily, POMGnT1, and TEM2. This domain, with two well-conserved glycine residues, was named GG and is composed of seven ß-strands and two α-helices, about 100 amino acid residues in size (5).
Hybid, the link to a mucopolysaccharide polymer
The structure of hyaluronan or hyaluronic acid (HA) was determined by Meyer in 1934 after its extraction from vitreous humor of bovine eyes. By chemical and enzymatic methods, they could establish that hyaluronan is a linear polymer built from repeating β-1,4-linked D-glucuronic acid (GlcA) and β-1,3-linked N-acetyl-D-glucosamine (GlcNAc) disaccharide units (6).
In 2012, Yoshida et al. was studying the depolymerization process of hyaluronan. Believing at first that the degradation mechanism of hyaluronic acid was due to the involvement of CD44 (as a receptor) and the enzymes HYAL1 and HYAL2 (as cleavers), they were unable to explain the rapid in-vivo catabolism of HA in the brain (where the HYAL1 and HYAL2 enzymes are not produced). Similarly, mice deficient in HYAL1 and HYAL2 did not show any accumulation of HA in the tissues.
Consequently, the team searched for genes whose expression increased significantly when they activated the in-vitro depolymerization mechanism in fibroblast cultures. Curiously enough, they stumbled upon KIAA1199 (7). KIAA1199 took the name of Hybid for Hyaluronan-binding protein, mediating the depolymerization of hyaluronan via the cell membrane-associated clathrin-coated pit endocytic pathway.
Yoshida et al. also demonstrated that KIAA1199 is overexpressed in tissues from arthritic joints, induced by inflammation. This discovery led many scientifics to investigate the correlation between Hybid and rheumatoid arthritis (RA) and osteoarthritis (OA). Yang et al. so demonstrated that Hybid is a potential biomarker for rheumatoid arthritis (8), while Deroyer and Chariot pointed out that Hybid was overexpressed in OA cartilages (9). Interestingly, Ding et al. suggested that inhibition of Hybid may represent a promising therapeutic target for OA (10).
But KIAA1199 plays also a role in cell mobility. And cell migration is the critical factor that precedes proliferation of many diseases, especially metastatic cancers.
CEMIP, the actor of cells migration
In 2013, Evensen et al demonstrated that KIAA1199 was upregulated in breast cancer patients and, contrary to what had been previously demonstrated, may be localized in endoplasmic reticulum. There, KIAA1199 induces cancer cell migration by a BiP–Ca2+–PKCα cascade (11). This implication has led the scientific community to refer KIAA1199 as a « Cell migration-inducing protein » or CEMIP.
KIAA1199 is over-expressed in excessively proliferated cancer tissues, including those from gastric cancer (12), and the silencing of CEMIP genes impacts the Wnt-signalling pathway and decreases the proliferation of colon cancer cells (13).
Since the discovery of exosomes in 1983, many teams have investigated their role in cell migration. In particular, McCready et al. reported that HSP90α exists on the surface of the exosomes derived from cancer cells with high invasive capacity, and enhance the invasive capacity of these abnormal cells (14). More recently, at the end of 2019, Rodrigues et al. found that CEMIP was highly expressed in brain metastatic cell-derived exosomes (15).
This intriguing protein hasn't finished being talked about.
REFERENCES
(1) Albert K Lliker, Ernst Ehlers, Albert Kolliker, Karl Theodor Ernst Von Seibold "Zeitschrift für wissenschaftliche Zoologie » 1851, 3, 109-169, "Recherches sur l'organe de l'ouïe des mammiferes" A. Corti.
(2) Otto Deiters, Untersuchungen über die Lamina spiralis membranacea: ein Beitrag zur Kenntniss des inneren Gehörorgans. Henry et Cohen, 1860
(3) Mikita Suyama, Takahiro Nagase, Osamu Ohara, HUGE: a database for human large proteins identified by Kazusa cDNA sequencing project, Nucleic Acids Research, Volume 27, Issue 1, 1 January 1999, Pages 338–339, https://doi.org/10.1093/nar/27.1.338
(4) Abe S, Usami S, Nakamura Y. 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. J Hum Genet. 2003;48(11):564-70. doi: 10.1007/s10038-003-0079-2. Epub 2003 Oct 24. PMID: 14577002.
(5) Guo J, Cheng H, Zhao S, Yu L. GG: a domain involved in phage LTF apparatus and implicated in human MEB and non-syndromic hearing loss diseases. FEBS Lett. 2006 Jan 23;580(2):581-4. doi: 10.1016/j.febslet.2005.12.076. Epub 2006 Jan 3. PMID: 16406369.
(6) Meyer, K. and Palmer, J.W. (1934) The polysaccharide of the vitreous humor. Journal of Biological Chemistry, 107, 629-634.
(7) Yoshida, H. et al. “KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.” Proceedings of the National Academy of Sciences 110 (2013): 5612 - 5617.
(8) Yang, X., Qiu, P., Chen, B., Lin, Y., Zhou, Z., Ge, R., … Wang, J. (2015). KIAA1199 as a potential diagnostic biomarker of rheumatoid arthritis related to angiogenesis. Arthritis Research & Therapy, 17(1). doi:10.1186/s13075-015-0637-y
(9) Deroyer, C., Charlier, E., Neuville, S. et al. CEMIP (KIAA1199) induces a fibrosis-like process in osteoarthritic chondrocytes. Cell Death Dis 10, 103 (2019). https://doi.org/10.1038/s41419-019-1377-8
(10) Ding, Qian-Hai, et al. "Knockdown of KIAA1199 Suppresses IL-1β-induced Cartilage Degradation and Inflammatory Responses in Human Chondrocytes Through the Wnt/β-catenin Signalling Pathway." International Immunopharmacology, vol. 73, 2019, pp. 203-211.
(11) Evensen NA, Kuscu C, Nguyen HL, et al. Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. J Natl Cancer Inst. 2013;105(18):1402-1416. doi:10.1093/jnci/djt224
(12) Matsuzaki S, Tanaka F, Mimori K, Tahara K, Inoue H, Mori M. Clinicopathologic significance of KIAA1199 overexpression in human gastric cancer. Ann Surg Oncol. 2009;16:2042–51.
(13) Birkenkamp-Demtroder K, Maghnouj A, Mansilla F, et al. Repression of KIAA1199 attenuates Wnt-signalling and decreases the proliferation of colon cancer cells. Br J Cancer. 2011;105(4):552-561. doi:10.1038/bjc.2011.268
(14) McCready J, Sims JD, Chan D, Jay DG Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activation. BMC Cancer. 2010 Jun 16; 10():294.
(15) Rodrigues G, Hoshino A, Kenific CM, et al. Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis. Nat Cell Biol. 2019;21(11):1403-1412. doi:10.1038/s41556-019-0404-4
