T-cadherin

CDH13
Available structures
Gene ontology
Molecular function	calcium ion binding; protein homodimerization activity; adiponectin binding; cadherin binding; metal ion binding; low-density lipoprotein particle binding; lipoprotein particle binding; cytoskeletal protein binding;
Cellular component	cytoplasm; membrane; focal adhesion; plasma membrane; perinuclear region of cytoplasm; caveola; anchored component of membrane; neuron projection; extracellular exosome; external side of plasma membrane; extracellular space; extracellular matrix; extracellular region; cell surface; catenin complex; synapse; collagen-containing extracellular matrix; GABA-ergic synapse;
Biological process	calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules; regulation of endocytosis; positive regulation of smooth muscle cell proliferation; negative regulation of cell adhesion; positive regulation of calcium-mediated signaling; positive regulation of endothelial cell proliferation; positive regulation of cell-matrix adhesion; positive regulation of cell migration; low-density lipoprotein particle mediated signaling; regulation of epidermal growth factor receptor signaling pathway; sprouting angiogenesis; response to organic substance; positive regulation of positive chemotaxis; keratinocyte proliferation; cell adhesion; Rho protein signal transduction; mitotic cell cycle; Rac protein signal transduction; localization within membrane; adherens junction organization; endothelial cell migration; negative regulation of cell population proliferation; lamellipodium assembly; homophilic cell adhesion via plasma membrane adhesion molecules; positive regulation of transcription by RNA polymerase II; cell morphogenesis; cell-cell junction assembly; cell-cell adhesion mediated by cadherin; cell-cell adhesion;
	Sources:Amigo / QuickGO
	ENSG00000140945
	ENSMUSG00000031841
	P55290
	Q9WTR5
NM_001220488; NM_001220489; NM_001220490; NM_001220491; NM_001220492;
	NM_001257
	NM_019707
NP_001207417; NP_001207418; NP_001207419; NP_001207420; NP_001207421;
	NP_001248
	NP_062681
	Wikidata
View/Edit Human	View/Edit Mouse

T-cadherin, also known as cadherin 13, H-cadherin (heart), and CDH13, is a unique member of the

GPI

anchor.

Unlike classical cadherins, which are necessary for

membrane receptors mediating signals received from the extracellular space, activate small GTPases and the beta-catenin/Wnt pathway, and play important roles in dynamic cytoskeleton reorganization, the GPI-anchored T-cadherin lacks direct contact with the cytoskeleton and therefore is not involved in cell–cell adhesion. It is instead involved in low-density lipoprotein (LDL) hormone-like effects on Ca²⁺ mobilization and increased cell migration

as well as phenotypic changes. The exact signaling partners and adaptor proteins recognized by T-cadherin remain to be elucidated.

Mediation of intracellular signaling in vascular cells

Though 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.

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

NF-kappaB

.

T-cadherin overexpression in ECs facilitates spontaneous cell migration, formation of stress fibers and change of the phenotype from quiescent to

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 lamellopodia

at the leading edge of migrating cells.

Functions in the vasculature

The 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

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, 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.^[5]

Regulation of cell growth

In 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.

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

gene promoter

region.

Transfection of T-cadherin negative

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

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

T-cadherin was originally cloned from chick embryo brain, where it was implicated as a negative guiding cue for motor axon projecting through the

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.