This article may be too technical for most readers to understand. (July 2017) |
T-cadherin, also known as cadherin 13, H-cadherin (heart), and CDH13, is a unique member of the cadherin protein family. Unlike typical cadherins that span across the cell membrane with distinct transmembrane and cytoplasmic domains, T-cadherin lacks these features and is instead anchored to the cell's plasma membrane through a GPI anchor.
Classical cadherins are central to cell–cell adhesion, critical for shaping tissues during embryonic development and maintaining tissue integrity in adults. They act as receptors that mediate cellular responses by transmitting signals from the extracellular environment to the intracellular machinery, thereby activating key pathways like the beta-catenin/Wnt pathway and influencing cytoskeletal reorganization. In contrast, T-cadherin is not involved in forming cell-cell junctions but participates in signaling pathways that modulate cellular responses to low-density lipoprotein (LDL) particles, affecting calcium signaling, cell migration, and phenotypic alterations. The identification of specific signaling partners and understanding the pathways influenced by T-cadherin are active areas of research, highlighting its potential role in vascular biology and disease pathologies.
Mediation of intracellular signaling in vascular cells
editThough T-cadherin can mediate weak adhesion in aggregation assays in vitro, the lack of intracellular domain suggests that T-cadherin is not involved in stable cell-cell adhesion. In vivo T-cadherin was detected on the apical cell surface of the chick intestinal epithelium. In cultures of transfected MDCS cells, T-cadherin was also expressed apically, whereas N-cadherin located basolaterally corresponded to the zone of cell contacts.[5]
The apical cell surface distribution of T-cadherin was proposed to possibly endow T-cadherin with recognition functions. In confluent cultures of vascular cells, T-cadherin was distributed equally over the entire cell surface, in contrast to VE-cadherin, which was restricted to the cell junctions. In migrating vascular cells, T-cadherin was located at the leading edge as revealed by confocal microscopy. The distribution of T-cadherin on the cell membrane is restricted to lipid rafts where it co-localizes with signal-transducing molecules. These data strongly implicates T-cadherin in intracellular signaling rather than adhesion.
Studying signaling effects of low density lipoproteins (LDL) in vascular smooth muscles (VSMCs), T-cadherin was isolated and identified as new LDL receptor using human aortic media and the ligand-blotting method.[6] The properties of T-cadherin as an LDL receptor were markedly different from the presently known types of LDL receptors. LDL binding to T-cadherin leads to the activation of Erk 1/2 tyrosine kinase and the nuclear translocation of NF-kappaB.
T-cadherin overexpression in ECs facilitates spontaneous cell migration, formation of stress fibers and change of the phenotype from quiescent to promigratory. T-cadherin expression results in LDL-induced migration of T-cadherin expressing cells compared to control. It is likely that T-cadherin regulates cell migration and phenotype via activation of small G-proteins with subsequent actin reorganization. RhoA/ROCK activation is necessary for cell contraction, stress fiber assembly and inhibition of spreading, while Rac is required for the formation of membrane protrusions and actin-rich lamellipodia at the leading edge of migrating cells.
Functions in the vasculature
editThe function of T-cadherin in situ, in normal conditions, and in pathology is still largely unknown. T-cadherin is highly expressed in the heart, aortic wall, neurons of the brain cortex and spinal cord and also in the small blood vessels in spleen and other organs.
Expression of T-cadherin is upregulated in atherosclerotic lesions and post-angioplasty restenosis —conditions associated with pathological angiogenesis. T-cadherin expression is upregulated in ECs, pericytes and VSMC of atherosclerotic lesions.
T-cadherin expression in arterial wall after balloon angioplasty correlates with late stages of neointima formation and coincidentally with the peak in proliferation and differentiation of vascular cells. It is highly expressed in adventitial vasa vasorum of injured arteries suggesting the involvement of T-cadherin in the processes of angiogenesis after vessel injury. These data implicate T-cadherin to be involved in regulation of vascular functioning and remodeling; however, the exact role of T-cadherin in neointima formation and atherosclerosis development is poorly understood.
LDL is not the only ligand for T-cadherin. High-molecular weight (HMW) complexes of adiponectin were suggested to be a specific ligand for T-cadherin. Adiponectin (adipocyte complement-related protein of 30 kDa) is a cytokine produced by adipose tissue and its deficiency is associated with metabolic syndrome, obesity, type II diabetes and atherosclerosis. Adiponectin binding to T-cadherin on vascular cells is associated with NF-kappa B activation. Two membrane adiponectin receptors with distant homology to seven-transmembrane spanning G-protein-coupled receptors, namely AdipoR1 and AdipoR2 were identified in several tissues,[7] but the University of Tokyo announced it was launching an investigation into anonymously made claims of fabricated and falsified data on the identification of AdipoR1 and AdipoR2 in 2016.[8]
Regulation of cell growth
editIn vitro T-cadherin is implicated in regulation of cell growth, survival and proliferation. In cultured VSMC and primary astrocytes, the expression of T-cadherin depends on proliferation status with maximum at confluency suggesting its regulation of cell growth by contact inhibition. Known mitogens such as platelet-derived growth factor (PDGF)-BB, epidermal growth factor (EGF) or insulin-like growth factor (IGF) elicit a reversible dose- and time-dependent decrease in T-cadherin expression in cultured VSMCs.[5]
Expression of T-cadherin leads to complete inhibition of subcutaneous tumor growth in nude mice. Seeding T-cadherin expressing cells on plastic coated with recombinant aminoterminal fragments of T-cadherin resulted in suppression of cell growth and was found to be associated with increased expression of p21. In T-cadherin deficient C6 glioma cell lines, its overexpression results in growth suppression involving p21Cip1/WAF1 production and G2 arrest.
T-cadherin loss in tumor cells is associated with tumor malignancy, invasiveness and metastasis. Thus, tumor progression in basal cell carcinoma, cutaneous squamous carcinoma, non-small cell lung carcinoma (NSCLC), ovarian cancer, pancreatic cancer, colorectal cancer correlates with downregulation of T-cadherin expression. In psoriasis vulgaris the hyperproliferation of keratinocytes also correlates with the downregulation of T-cadherin expression. The mechanism for T-cadherin suppression is associated with allelic loss or hypermethylation of the T-cadherin gene promoter region.
Transfection of T-cadherin negative neuroblastoma TGW and NH-12 cells with T-cadherin results in their loss of mitogenic proliferative response to epidermal growth factor (EGF) growth stimulation. Re-expression of T-cadherin in human breast cancer cells (MDAMB435) in culture, which originally do not express T-cadherin, results in the change of the phenotype from invasive to normal epithelial-like morphology. Thus, it was hypothesized that T-cadherin functions as a tumor-suppressor factor; inactivation of T-cadherin is associated with tumor malignancy, invasiveness and metastasis.
However, in other tumors T-cadherin expression could promote tumor growth and metastasis. In primary lung tumors the loss of T-cadherin was not attributed to the presence of metastasis in lymph nodes, and in osteosarcomas T-cadherin expression was correlated with metastasis. Furthermore, T-cadherin overexpression was found to be a common feature of human high grade astrocytomas and associated with malignant transformation of astrocytes. Hetezygosity for NF1 (neurofibromatosis 1) tumor suppressor resulting in reduced attachment and spreading and increased motility also coincides with upregulated T-cadherin expression.
Data show that HUVEC cells overexpressing T-cadherin after adenovirus infection enter S-phase more rapidly and exhibit increased proliferation potential. T-cadherin expression increases in HUVEC under conditions of oxidative stress, and production of reactive oxygen species (ROS) contributes to T-cadherin elevated expression. T-cadherin overexpression in HUVEC leads to higher phosphorylation of Phosphatidylinositol 3-kinase (PIK3) – _target of Akt, and mTOR – _target p70S6K (survival pathway regulator), resulting in reduced levels of caspase activation and increased survival after exposure to oxidative stress.[clarification needed] It was suggested that in vascular cells T-cadherin performs a protective role against stress-induced apoptosis.
Tumor cells can regulate gene expression in growing vessels and the surrounding stroma during tumor neovascularization. T-cadherin expression was found to be altered in tumor vessels: in Lewis carcinoma lung metastasis the expression of T-cadherin was upregulated in blood vessels penetrating the tumor, while T-cadherin was not detected in the surrounding tumor tissue. In tumor neovascularization of hepatocellular carcinoma (HCC) T-cadherin is upregulated in intratumoral capillary endothelial cells, whereas in surrounding tumor tissue as well as in normal liver no T-cadherin could be detected. The increase in T-cadherin expression in endothelial cell in HCC was shown to correlate with tumors progression. Presumably, T-cadherin could play a navigating role in the growing tumor vessels, which in the absence of contact inhibition from the stromal cells, grow into the surrounding tumor tissue.
Guiding molecules in vascular and nervous systems
editT-cadherin was originally cloned from chick embryo brain, where it was implicated as a negative guiding cue for motor axon projecting through the somitic sclerotome and presumably for migrating neural crest cells . As a substrate or in soluble form, T-cadherin inhibits neurite outgrowth by motor neurons in vitro supporting the assumption that T-cadherin acts as a negative guiding molecule in the developing nervous system.
Considering that the maximal expression of T-cadherin has been observed in nervous and cardiovascular systems, it is likely that T-cadherin is involved in guiding the growing vessel as well. The mechanism of T-cadherin mediated negative guidance in nervous system involves homophilic interaction and contact inhibition; in vascular system it is supposed that T-cadherin expressing blood vessels would avoid T-cadherin expressing tissues.
References
edit- ^ a b c GRCh38: Ensembl release 89: ENSG00000140945 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031841 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b Imai-Okano K, Hirano S (2016). "Various atypical cadherins: T-cadherin, RET, calsyntenin, and 7D-cadherin.". The Cadherin Superfamily: Key Regulators of Animal Development and Physiology. Tokyo: Springer. pp. 277–311. doi:10.1007/978-4-431-56033-3_11. ISBN 978-4-431-56033-3.
- ^ Resink TJ, Kuzmenko YS, Kern F, Stambolsky D, Bochkov VN, Tkachuk VA, et al. (December 1999). "LDL binds to surface-expressed human T-cadherin in transfected HEK293 cells and influences homophilic adhesive interactions". FEBS Letters. 463 (1–2): 29–34. doi:10.1016/S0014-5793(99)01594-X. PMID 10601632.
- ^ Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. (June 2003). "Cloning of adiponectin receptors that mediate antidiabetic metabolic effects". Nature. 423 (6941): 762–769. doi:10.1038/nature01705. PMID 12802337.
- ^ University of Tokyo to investigate data manipulation charges against six prominent research groups ScienceInsider, Dennis Normile, Sep 20, 2016
Further reading
edit- Ranscht B, Dours-Zimmermann MT (September 1991). "T-cadherin, a novel cadherin cell adhesion molecule in the nervous system lacks the conserved cytoplasmic region". Neuron. 7 (3): 391–402. doi:10.1016/0896-6273(91)90291-7. PMID 1654948.
- Angst BD, Marcozzi C, Magee AI (February 2001). "The cadherin superfamily: diversity in form and function". Journal of Cell Science. 114 (Pt 4): 629–641. doi:10.1242/jcs.114.4.629. PMID 11171368.
- Angst BD, Marcozzi C, Magee AI (February 2001). "The cadherin superfamily". Journal of Cell Science. 114 (Pt 4): 625–626. doi:10.1242/jcs.114.4.625. PMID 11171365.
- Takeuchi T, Ohtsuki Y (October 2001). "Recent progress in T-cadherin (CDH13, H-cadherin) research". Histology and Histopathology. 16 (4): 1287–1293. doi:10.14670/HH-16.1287. PMID 11642747.
- Suzuki S, Sano K, Tanihara H (April 1991). "Diversity of the cadherin family: evidence for eight new cadherins in nervous tissue". Cell Regulation. 2 (4): 261–270. doi:10.1091/mbc.2.4.261. PMC 361775. PMID 2059658.
- Tanihara H, Sano K, Heimark RL, St John T, Suzuki S (April 1994). "Cloning of five human cadherins clarifies characteristic features of cadherin extracellular domain and provides further evidence for two structurally different types of cadherin". Cell Adhesion and Communication. 2 (1): 15–26. doi:10.3109/15419069409014199. PMID 7982033.
- Lee SW (July 1996). "H-cadherin, a novel cadherin with growth inhibitory functions and diminished expression in human breast cancer". Nature Medicine. 2 (7): 776–782. doi:10.1038/nm0796-776. PMID 8673923. S2CID 26741373.
- Tkachuk VA, Bochkov VN, Philippova MP, Stambolsky DV, Kuzmenko ES, Sidorova MV, et al. (January 1998). "Identification of an atypical lipoprotein-binding protein from human aortic smooth muscle as T-cadherin". FEBS Letters. 421 (3): 208–212. doi:10.1016/S0014-5793(97)01562-7. PMID 9468307. S2CID 26099158.
- Kremmidiotis G, Baker E, Crawford J, Eyre HJ, Nahmias J, Callen DF (May 1998). "Localization of human cadherin genes to chromosome regions exhibiting cancer-related loss of heterozygosity". Genomics. 49 (3): 467–471. doi:10.1006/geno.1998.5281. PMID 9615235.
- Philippova MP, Bochkov VN, Stambolsky DV, Tkachuk VA, Resink TJ (June 1998). "T-cadherin and signal-transducing molecules co-localize in caveolin-rich membrane domains of vascular smooth muscle cells". FEBS Letters. 429 (2): 207–210. doi:10.1016/S0014-5793(98)00598-5. PMID 9650591. S2CID 18838349.
- Sato M, Mori Y, Sakurada A, Fujimura S, Horii A (July 1998). "The H-cadherin (CDH13) gene is inactivated in human lung cancer". Human Genetics. 103 (1): 96–101. doi:10.1007/s004390050790. PMID 9737784. S2CID 30812156.
- Sato M, Mori Y, Sakurada A, Fujimura S, Horii A (1999). "A GT dinucleotide repeat polymorphism in intron 1 of the H-cadherin (CDH13) gene". Journal of Human Genetics. 43 (4): 285–286. doi:10.1007/s100380050093. PMID 9852687.
- Resink TJ, Kuzmenko YS, Kern F, Stambolsky D, Bochkov VN, Tkachuk VA, et al. (December 1999). "LDL binds to surface-expressed human T-cadherin in transfected HEK293 cells and influences homophilic adhesive interactions". FEBS Letters. 463 (1–2): 29–34. doi:10.1016/S0014-5793(99)01594-X. PMID 10601632. S2CID 5950399.
- Takeuchi T, Misaki A, Liang SB, Tachibana A, Hayashi N, Sonobe H, et al. (April 2000). "Expression of T-cadherin (CDH13, H-Cadherin) in human brain and its characteristics as a negative growth regulator of epidermal growth factor in neuroblastoma cells". Journal of Neurochemistry. 74 (4): 1489–1497. doi:10.1046/j.1471-4159.2000.0741489.x. PMID 10737605. S2CID 35138858.
- Niermann T, Kern F, Erne P, Resink T (October 2000). "The glycosyl phosphatidylinositol anchor of human T-cadherin binds lipoproteins". Biochemical and Biophysical Research Communications. 276 (3): 1240–1247. doi:10.1006/bbrc.2000.3465. PMID 11027617.
- Ivanov D, Philippova M, Antropova J, Gubaeva F, Iljinskaya O, Tararak E, et al. (March 2001). "Expression of cell adhesion molecule T-cadherin in the human vasculature". Histochemistry and Cell Biology. 115 (3): 231–242. doi:10.1007/s004180100252. PMID 11326751. S2CID 24818598.
- Zhou S, Matsuyoshi N, Liang SB, Takeuchi T, Ohtsuki Y, Miyachi Y (June 2002). "Expression of T-cadherin in Basal keratinocytes of skin". The Journal of Investigative Dermatology. 118 (6): 1080–1084. doi:10.1046/j.1523-1747.2002.01795.x. PMID 12060406.
- Toyooka S, Toyooka KO, Harada K, Miyajima K, Makarla P, Sathyanarayana UG, et al. (June 2002). "Aberrant methylation of the CDH13 (H-cadherin) promoter region in colorectal cancers and adenomas". Cancer Research. 62 (12): 3382–3386. PMID 12067979.
- Takeuchi T, Liang SB, Matsuyoshi N, Zhou S, Miyachi Y, Sonobe H, et al. (August 2002). "Loss of T-cadherin (CDH13, H-cadherin) expression in cutaneous squamous cell carcinoma". Laboratory Investigation; A Journal of Technical Methods and Pathology. 82 (8): 1023–1029. doi:10.1097/01.lab.0000025391.35798.f1. PMID 12177241.
- Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–16903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Takeuchi T, Liang SB, Ohtsuki Y (December 2002). "Downregulation of expression of a novel cadherin molecule, T-cadherin, in basal cell carcinoma of the skin". Molecular Carcinogenesis. 35 (4): 173–179. doi:10.1002/mc.10088. PMID 12489108. S2CID 20534335.
- Roman-Gomez J, Castillejo JA, Jimenez A, Cervantes F, Boque C, Hermosin L, et al. (April 2003). "Cadherin-13, a mediator of calcium-dependent cell-cell adhesion, is silenced by methylation in chronic myeloid leukemia and correlates with pretreatment risk profile and cytogenetic response to interferon alfa". Journal of Clinical Oncology. 21 (8): 1472–1479. doi:10.1200/JCO.2003.08.166. PMID 12697869.
External links
edit- T-cadherin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- CDH13 human gene location in the UCSC Genome Browser.
- CDH13 human gene details in the UCSC Genome Browser.