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FLASH GENE

Symbol

CDH2

contributors: shn/pgu - updated : 19-11-2019

HGNC name	cadherin 2, type 1, N-cadherin (neuronal)
HGNC id	1759

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ACOGS ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects) ARVC14 arrhythmogenic right ventricular cardiomyopathy 14
Location	18q12.1      Physical location : 25.530.929 - 25.757.445
Synonym name	N-cadherin
	CD325 antigen
	neural cadherin
	calcium-dependent adhesion protein, neuronal
Synonym symbol(s)	NCAD, CDHN, CD325, CDw325, N-CAD, NCDH

DNA

TYPE	functioning gene
STRUCTURE	244.25 kb     16 Exon(s)

10 Kb 5' upstream gene genomic sequence study

text structure

a CCG repeat in 5'utr

MAPPING

cloned

Y

linked

N

status

confirmed

Map	cen - D18S478 - D18S1151 - CDH2 - D18S847 - D18S463 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001792 16 - 4016 NP_001783 97 906 - 2018 30242148 NM_001308176 15 - 3908 NP_001295105 - 875 - 2018 30242148

EXPRESSION

Type

widely

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       predominantly Homo sapiens Digestive intestine small intestine       Endocrine adrenal gland       highly   neuroendocrine pituitary     highly Nervous brain diencephalon amygdala     Mus musculus   brain limbic system hippocampus     Mus musculus   brain diencephalon hypothalamus     Mus musculus Reproductive male system testis     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular smooth vessel     Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	expressed at the time of gastrulation and neurulation

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a N terminal hydrophobic domain, large N-terminal extracellular domain composed of five tandem repeat domains, termed cadherin repeats that contain four Ca2+-binding sites, and are involved in homotypic protein–protein interactions
	a transmembrane (1TM) segment and a highly conserved cytoplasmic tail
	cytoplasmic domain containing two main binding regions, the C-terminal domain (CTD) and the juxtamembrane domain (JMD)

secondary structure

a cadherin pro-region, five EC repeats of about 110 residues, each of which fold into seven anti-parallel beta strands arranged into two beta sandwich folds, a transmembrane region and a cytoplasmic tail

conjugated

GlycoP , RiboP

HOMOLOGY

interspecies	ortholog to Cdh2, Mus musculus
	ortholog to Cdh2, Rattus norvegicus
	ortholog to cdh2, Danio rerio
	ortholog to CDH2, Pan troglodytes

Homologene

FAMILY

cadherin superfamily

CATEGORY

adhesion

SUBCELLULAR LOCALIZATION	plasma membrane,junction,tight
	plasma membrane,junction,adherens
	intracellular
	intracellular,cytoplasm,organelle,lumen
	intracellular,cytoplasm,organelle,endoplasmic reticulum
text	observed in the cytoplasm, was actively internalized by endocytosis

basic FUNCTION	N-cadherin plays a critical role in early heart development as well as in other morphogenetic processes
	putatively involved in synaptic adhesion, axon outgrowth
	and guidance
	cell-cell or cell-ECM interactions
	required for establishment of left-right asymmetry during gastrulation
	maybe involved in establishment of embryonic left-right asymetry
	regulates dendritic spine morphogenesis and related synaptic functions, presumably cooperating with cadherin-independent adhesive mechanisms to maintain spine-axon contacts
	mediates apical adhesion between retina epithelial cells
	calcium-dependent cell adhesion molecule that is associated with invasive tumors in breast cancer
	modifies KCNA5 activity and is thus a novel candidate signaling molecule participating in the regulation of a variety of functions including cardiac action potential and vascular tone
	plays a pivotal role in the maintenance of the progenitor phenotype in cultured limbal epithelial cells
	cell adhesion molecules that interacts in a homophilic Ca2+-dependent manner through its extracellular ectodomains
	having specific function in the maintenance of dendrite arbors
	CDH2 and CDH11 are crucial regulators of postnatal skeletal growth and bone mass maintenance, serving overlapping, yet distinct, functions in the osteogenic lineage
	with NLGN1, cooperate to control vesicle clustering at nascent synapses
	intimately involved in neuronal cell adhesion, signaling, differentiation and synapse function
	acts by postsynaptically accumulating neuroligin-1 and activating its function via the scaffolding molecule MAGI2, leading, in turn, to presynaptic vesicle clustering
	in neurons, is required to enable neuroligin-1 to exert its vesicle cluster-inducing effect
	key cell adhesion molecule implicated in chondrogenic differentiation
	PCDH19 and CDH2 function together to regulate cell adhesion and to mediate morphogenetic movements during brain development
	important role during dendrite arborization, axon guidance, and synaptogenesis
	ATP-sensitive protein that is associated with altered Huntington disease CAG striatal cell adhesion and neuritogenesis
	integrator of adhesion and cytoskeletal signaling required for proper neuronal cell development and synaptic function
	important for multipolar neurons to polarize their migration toward the cortical plate
	regulates the proliferation of DA (dopaminergic) progenitors and the differentiation of DA neurons through canonical WNT-CTNNB1 signaling in the ventral midbrain (vMB)
	is a cell adhesion molecule which is enriched at synapses
	relocalizes from the periphery to the center of the synapse after transient synaptic stimulation in hippocampal neurons
	regulates molecular organization of excitatory and inhibitory synaptic circuits in adult hippocampus
	functional role of CDH2 adherens junctions (AJ) in vasomotor regulation
	plays a vital role in cell adhesion, making it a biologically plausible candidate gene in ARVC pathogenesis (PMID
	regulates signaling mechanisms required for lens fiber cell elongation and lens morphogenesis
	important role in neurulation, brain development and regulation of synaptic function
	importance of CDH2 in angiogenesis
	CDH2-mediated interactions are necessary for migration and survival during the postmitotic phase of interneuron development
	essential roles in neural development include neuronal migration and axon pathfinding

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	constituent of transmembrane glycoprotein component of adherens junction
	forms a molecular complex with axin1 and LRP5 involving the LRP5 cytoplasmic tail domain
	functionally interacts with LRP6 and axin1 in osteoblasts

INTERACTION

DNA

RNA

small molecule

protein	forms heterodimers R-cadherins
	protein tyrosine phosphatase, non-receptor type 1, PTPN1
	in retinoblastoma and normal retina N-cadherin associated with alpha-catenin and beta-catenin
	glutamate receptor 6, GLUR6
	Presenilin1, PS1
	RICS-beta-catenin complex
	cell adhesion molecule-related/down-regulated by oncogenes; surface glycoprotein, Ig superfamily member, CDO and Boc homolog (mouse), BOC
	cadherin-11, alpha- and beta-catenin, plakoglobin (proportions variable among species), p120ctn and vinculin
	hemophilic, calcium dependent interactions
	interacting by its C terminus with the cytoskeleton via beta-catenin
	Wnt coreceptor LRP5 and regulates canonical Wnt/beta-catenin signaling in osteoblasts
	CDH2-axin1-LRP5 interaction negatively regulates Wnt/beta-catenin signaling and is critical in the regulation of osteoblast function, bone formation, and bone mass
	CDCP1
	cleaved specifically by the disintegrin and metalloproteinase ADAM10 in its ectodomain
	on GRIA2, B3GAT1 regulates cell surface stability of GRIA2 by modulating the interaction with CDH2
	N-cadherins form homophilic interactions with N-cadherins on opposing membranes and these molecular interactions mediate the effect of neuronal activity on promoting dendrite growth, an important aspect of coordinated neural circuit development
	mechanistic link among the cell adhesion molecule, CDH2, the actin-binding scaffold protein, CTTN, and KCNA5 remodeling in the heart
	its expression facilitates cis-dimerization of APP (
	SHROOM3 and CDH2 function cooperatively downstream of PITX2 to directly regulate cell shape changes necessary for early gut tube morphogenesis
	adhesion by the PCDH19-CDH2 complex was unaffected by mutations that disrupt CDH2 homophilic binding but was inhibited by a mutation in PCDH19
	CDH2 engagement mediates neuronal cell survival by enhancing the MAP kinase pathway and down-regulating the pro-apoptotic protein BCL2L11
	BEX2 promoted the progression of glioma by promoting cell migration and invasion, and these effects might be mediated by CDH2 and MMP2
	CEACAM1 inhibit cell-matrix adhesion and promote cell motility and CDH2 is a crucial protein involved in the processes
	CDH2 specifically interacts with FBXO45 through two consensus motifs overlapping the site of calcium-binding and dimerization of the cadherin molecule
	function of desmoplakin in motor nerve regeneration by linking CDH2 to intermediate filaments in regenerating motor axons
	CDH2 and CDH11 act as regulators of stem cell fate decisions
	CDON promotes neural crest migration by regulating CDH2 localization
	CD82 regulates bone marrow homing of acute myeloid leukemia by modulating the molecular organization of CDH2
	new role for CTNND1 bound to the CDH2 precursor ensuring its trafficking through the biosynthetic pathway towards the cell surface
	AMOTL1 is an essential effector of the CDH2 mediated endothelial/pericyte junctional complex
	EXOC4 regulates CDH2 expression by controlling SMAD3 and SMAD4 expression at the basal transcriptional level, thereby modulating cell migration and adhesion
	periodic expression of PCDH8 in the anterior presomitic mesoderm (PSM) triggers rhythmic endocytosis of CDH2, allowing for segmental de-adhesion and individualization of somites
	RELN transiently (and not persistently) promotes CDH2-mediated neuronal aggregation
	INVS could upregulate the expression of CDH2, VIM, MMP2, and MMP9
	PKD1 enhances the stability of CDH2 on cell membrane and promotes synapse morphogenesis and synaptic plasticity in an activity-dependent manner
	CDH2 promotes neurite branching and it is required for three synaptic organizers, NLGN1, leucine-rich repeat transmembrane protein 2 (LRRTM2), and CADM1 to stimulate presynaptic differentiation
	interaction of NECTIN2 with CDH2
	GJA1 controls neural crest cell migration by directly regulating CDH2 transcription
	CDH2-signaling via TRIO assembles adherens junctions to restrict endothelial permeability

cell & other

REGULATION

Other	regulated by PSEN1 (PSEN1-mediated delivery of CDH2 to the plasma membrane is important for exerting its physiological function, and control of the state of cell-cell contact)
	cleaved by ADAM10 (cleavage of N-cadherin is essential for chondrocyte differentiation)
	upregulated by RAP1 (

ASSOCIATED DISORDERS

corresponding disease(s)

ACOGS , ARVC14

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in ductal carcinomas, decreased levels in primary tumors correlate with local recurrence and death in long-term follow-up of patients constitutional         of either CDH2 or LIN7C disrupts neural tube formation constitutional         loss of CDH2 alters the actin cytoskeleton, leading to a decrease in the cortical actin-binding protein, CTTN, which associates with KCNA5 channel and regulates its function in the heart tumoral     --low   by promoter methylation in colorectal cancer patients constitutional     --over   partially attenuated nucleus pulposus (NP) cell senescence, decreased ROS content and inhibited the activation of the NFKB1 pathway under the high glucose condition

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed diabete type 2   is a potential therapeutic target to slow Diabetes-mediated disc nucleus pulposus (NP) degeneration

ANIMAL & CELL MODELS

	Homozygous N-cadherin mutant embryos die by Day 10 of gestation
	in adult mice loss of N-cadherin in osteolineage cells favors bone formation