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FLASH GENE

Symbol

CLDN4

contributors: mct - updated : 21-01-2017

HGNC name	claudin 4
HGNC id	2046

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	1.83 kb     1 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site
text structure	TWIST1 binds to an E-box site of the CLDN4 promoter

MAPPING

cloned

Y

linked

N

status

provisional

regionally located

situated in the Williams-Beuren critical region

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001305 1 - 1846 NP_001296 22 209 - 1999 10366445

EXPRESSION

Type

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 Lymphoid/Immune thymus       highly Homo sapiens Reproductive male system male genital tract epididymis     Homo sapiens Respiratory lung         Homo sapiens Urinary kidney tubule collecting duct     Homo sapiens   kidney nephron renal capsule     Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune lymphocyte Homo sapiens Respiratory alveolar cell type 1 Homo sapiens Respiratory epithelial cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

neonatal

Text	infant brain

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	four putative transmembrane segments
	a cytoplasmic region, which has important roles in the formation and function of tight junctions, but dispensable for the TCR costimulatory activity

mono polymer

monomer

HOMOLOGY

Homologene

FAMILY

claudin family

CATEGORY

adhesion , structural protein

SUBCELLULAR LOCALIZATION	plasma membrane,junction,tight
text	integral membrane protein

basic FUNCTION	tight junction specific obliteration of the intercelular space
	creating charge specific channels in the paracellular space
	forms a paracellular chloride channel in the collecting duct
	essential role in the formation and maintenance of tight junctions
	integral membrane cell-junction protein
	act as molecular mediator of embryo implantation
	interaction with CLDN8 are required for the anion-selective paracellular channel in the collecting duct
	forms a paracellular chloride channel in the collecting duct
	with CLDN8 are required for paracellular reabsorption of Cl–, interacted in cell membranes
	roles for CLDN3 and CLDN4 in alveolar epithelial barrier function
	potentially promotes the recruitment of free CD4/LCK to the TCR proximity on antigen engagement directly or indirectly
	both CLDN3 and CLDN4 mediate interactions with other cells that restrain growth and metastatic potential by sustaining expression of E-cadherin and limiting CTNNB1 signaling
	plays an important role in maintaining the homeostatic integrity of normal urothelium
	tight junction protein regulating the paracellular permeability of cell layers
	CLDN4 and FUT4 are representative genes that participate in modulating trophoblast mobility

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component	major structural components of tight junction (TJ) strands
	CLDN4 and CLDN16 may participate not in homodimers but in obligate heterodimers with selected other claudins

INTERACTION

DNA

RNA

small molecule

protein	interacting with LIF (are associated with assisted reproduction outcome)
	in the collecting duct cells, the assembly of CLDN4 into tight junctions strands required its interaction with CLDN8
	accumulates CLDN1 and CLDN3 in TJs to enhance cell-cell contact in renal tubular epithelial cells
	GRHL2 regulates epithelial morphogenesis through transcriptional up-regulation of CLDN3 and CLDN4, as well as of RAB25, which increases the CLDN4 protein and its localization at TJs
	EGF controls the levels of CLDN2 and CLDN4 proteins and mRNAs through SRC and STAT3 activity
	CLDN4 serves to restrain pro-oncogenic signaling from EPHA2 by limiting the activity of CTNNB1 and PI3K and preventing phosphorylation of EPHA2 on S897 by AKT1 0)
	GRHL2/OVOL2 network controlling CLDN4 and RAB25 expression that facilitates lumen expansion and barrier formation in subtypes of renal epithelia
	REG1A may play a role in the maintenance of mucosal barrier function by inducing tight junction proteins such as CLDN3 and CLDN4

cell & other

REGULATION

induced by

E-protein activity in the later stages of DP thymocytes before positive selection, suggesting that it increases the efficiency of positive selection through unique TCR costimulatory activity

repressed by

TWIST1 (up-regulation of TWIST1 decreased both gene and protein expression levels of endogenous CLDN4 and the suppression was mediated by direct binding of TWIST1 to the canonical E-box in the promoter region of CLDN4)

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in colorectal cancer tumoral     --over   in ovarian carcinoma tumoral     --over   in intestinal-type gastric cancer ( lower in diffuse-type gasric cancer) tumoral     --over   in prostate cancer, highly expressed in lower grade lesions than in higher grade tumoral     --low   in highly aggressive esophageal cancer and the reduction of CLDN4 leads to the resultant disruption of tight junctions that may be associated with EMT constitutional     --over   in the placentas of diabetic mothers and in toxaemia

Susceptibility

Variant & Polymorphism

Candidate gene
Marker	very useful marker for distinguishing mesothelioma and adenocarcinoma, even if histological specimens are small, as in biopsies that contain limited numbers of tumor cells
	highly specific and sensitive immunohistochemical marker for assisting in distinguishing epithelioid mesotheliomas from metastatic carcinomas to the serosal membranes (pMID: 23596113)
Therapy target
	System Type Disorder Pubmed cancer     anti-claudin-3 and -4 bispecific monoclonal antibody shows promise in the development of a diagnostic and therapeutic antibody for cancers cancer digestive colon potential markers and therapy target in colorectal cancer cancer reproductive prostate useful as a potential marker and therapeutic target for prostate cancer metastases

ANIMAL & CELL MODELS

progressive hydronephrosis in Cldn4(-/-) mice arises from urinary tract obstruction due to urothelial hyperplasia