Cleavage of transmembrane junction proteins and their role in regulating epithelial homeostasis

Figures & data

Figure 1. E-cadherin cleavage and its influence on epithelial homeostasis. This figure summarizes extracellular and intracellular cleavage of E-cadherin as detailed in the review.

Figure 2. Potential cleavage sites in transmembrane junctional proteins. These figures demonstrate potential cleavage sites of representative transmembrane junctional proteins in epithelial cells. (A) Tight junction proteins; (B) E-cadherin; (C) desmoglein

Table 1. Extracellular cleavage of transmembrane junction proteins in epithelial cells

Junction protein	Protease		Model epithelial cell line	Functional output of cleavage product	Stimulus	Reference
Claudin-2	Serine protease		T84 (Colon)		IFN-γ	29
EpCAM	ADAM17 (TACE)		HEK293 (Kidney), FaDu (Hypopharynx)			93
	γ-secretase		HEK293 (Kidney), HT29 (Colon)			124
JAM-A	ADAM10, 17 (TACE)		HEK293 (Kidney)	Neutrophil transmigration↓	PMA	35
Occludin	MMP		MDCK (Kidney)	Barrier function↓	Methyl-β-cyclodextrin	125
	MMP2		Primary human ectocervical epithelial cells, CaSki (Cervix)			126
	MMP7		Primary human normal vaginal-cervical epithelial cells		Estrogen	127
	MMP9		Human corneal epithelial cells, MMP9 knockout mouse			66
			Human corneal epithelial cells		Extracellular matrix metalloprotease inducer	28
	Serine protease	Plasmin	Primary human ectocervical epithelial cells, CaSki (Cervix)			126
	Bacterial protease	Aerolysin	HT29/B6 (Colon)			32
		Haemagglutinin/ protease	MDCK (Kidney)			31
	Protease K		Primary human ectocervical epithelial cells, CaSki (Cervix)	Barrier function↓		126
E-cadherin	MMP	Membrane-bound	SW480, HT29 (Colon), A431 (Skin), TE12, TE13 (Esophagus)		Mechanical scraping, ionomycin	84
	MMP2		LNCapFGC (Prostate)	Cell proliferation↓	PKD1	128
	MMP3		MDCK (Kidney), DU145 (Breast)	Cell invasion↑, cell-cell adhesion↓	PMA	40
			SCp2, SCg6 (Breast)	Cell-cell adhesion↓		73
			HC11 (Breast)	Cell invasion↑	FK506-binding domain dimerizer (AP20187)	74
	MMP7		MDCK (Kidney)	Cell-cell adhesion↓, cell migration↑, cell polarization↓, cell proliferation↑		129
			MDCK (Kidney), MCF-7 (Breast)	Cell invasion↑, cell-cell adhesion↓	PMA	40
			LNCaP-FGC (Prostate)	Cell-cell adhesion↓, cell invasion↑	HGF/SF	39
			A549 (Lung)	Cell migration↑		130
			NUGC-3, MKN-28 (Stomach)	Cell invasion↑	HGF	131
	MMP9		OVCA433 (Ovary)	Barrier function↓, cell-cell adhesion↓	Bead-immobilized α3 or β1 integrin antibody	41
			MDCK (Kidney), DU145 (Breast)	Cell proliferation↓	PKD1	128
			SCC10A (Head and neck)	Cell migration↑, cell invasion↑	EGF	132
	Meprinß		MDCK (Kidney), Caco-2 (Colon)	Cell-cell adhesion↓		133
	ADAM10		HaCaT (Skin)	Cell migration↑		43
			Primary human keratinocyte cells		TGF-β, IL-1β, LPS, IFN-γ + TNF-α	134
			NCI-N87 (Stomach)		Helicobacter pylori	135
			MDCK (Kidney)		Ephrin-B1	136
	ADAM15		SKBr3 (Breast)	Cell prolieration↑, cell migration↑		77
	γ-secretase		Caco-2 (Colon)	Barrier function↓	Candida albicans	137
	Serine protease	Kallikrein 6	HEK293 (Kidney)	Cell-cell adhesion↓		138
		Kallikrein 7	BxPC-3 (Pancreas)	Cell invasion↑, cell-cell adhesion↓		63
		Plasmin	MDCK (Kidney)	Cell-cell adhesion↓, cell invasion↑		62
			OVCA429 (Ovary)	Cell invasion↑	LPA	115
	Bacterial protease	Fragilysin	HT29/C1 (Colon)			45
		Gingipain	MDCK (Kidney)			46
		HtrA	MKN-28 (Stomach)	Bacteria invasion↑, bacterial transmigration↑		44
	Leukocyte elastase		Rat pancreatic tissue, primary rat pancreatic acinar cells	Leukocyte transmigration↑, cell-cell adhesion↓	Cerulein	139
	Cysteine protease	Cathepsins: B, S, L	Mouse pancreatic cancer model	Cell invasion↑		140
Nectin-1α	MMP		MDCK (Kidney)		TPA, HGF/SF	48
Nectin-4	ADAM17 (TACE)		CHO (Ovary), T47D (Breast)		PMA	49
Desmoglein 1	MMP		A431 (Skin)		UV	141
	Serine protease	Plasmin	Human skin tissue			142
		Exfoliative toxin A	Mouse skin	Cell-cell adhesion↓		53
			HaCaT (Skin)			54
			Organotypic raft model of human epidermis, primary human epidermal keratinocytes			50 , 52
		Kallikrein 5	SCC25 (Tongue)			51
Desmoglein 2	MMP		SKCO-15 (Colon)			86
	ADAM10		CHO (Ovary), A431 (Skin), ADAM10 knockout mouse		EGF	58
	ADAM17 (TACE)		SCC68 (Skin)	Cell-cell adhesion↓		143
			CHO (Ovary), A431 (Skin), ADAM10 knockout mouse		EGF	58
			A431 (Skin)			144
	Serine protease	Kallikrein 7	Panc-1, BxPC-3 (Pancreas)			145
		Matriptase	HCT-116 (Colon)	Cell-cell adhesion↓		57
Desmoglein 3	MMP		HaCaT (Skin)		Staurosporine	146
Desmocollin 3

Table 2. Intracellular cleavage of transmembrane junction protein in epithelial cells

Junction protein	Protease		Model epithelial cell line	Functional output of cleavage product	Stimulus	Reference
Claudin-2	Serine protease			T84 (Colon)	IFNγ	29
EpCAM	γ-secretase	Presenilin 2	HEK293 (Kidney)	Cell proliferation↑	Extracellular cleavage product of EpCAM	93
			HEK293 (Kidney), HT29 (Colon)			124
Occludin	MMP		MDCK (Kidney)	Barrier function↓	Methyl-β-cyclodextrin	125
	Cysteine protease	Calpain	Caco-2 (Colon), HaCaT (Skin)	Barrier function↓, bacterial translocation	Streptolysin S	82
			16 HBE, 1HAEo (Lung/Bronchus)	Polymorphonuclear leukocytes (PMNs) transmigration	Toll-like receptor 2 ligands	83
		Der p 1	MDCK (Kidney), 16HBE14o (Lung/Bronchus)	Barrier function↓		30
E-cadherin	MMP7		MDCK (Kidney)	Cell-cell adhesion↓, cell migration↑, cell polarization↓, cell proliferation↑		129
	MMP	Membrane-bound	SW480, HT29 (Colon), A431 (Skin), TH12, TE13 (Esophagus)		Mechanical scraping, ionomycin	84
	MT1-MMP (MMP14)		NRK-52E (Kidney)	Cell-cell adhesion↓		147
	ADAM10		Primary human keratinocyte cells		TGFβ, IL-1β, LPS, IFNγ + TNFα	134
	γ-secretase		Caco-2 (Colon)	Barrier function↓	Candida albicans	137
			T47D, MCF-7 (Breast)	Cell-cell adhesion↓	Staurosporine	148
			A431 (Skin), MCF-7 (Breast), MDCK (Kidney)			91
		Presenilin 1	Murine embryonic fibroblast, SW480 (Colon)			90
			A431 (Skin)	Cell-cell adhesion↓	Ionomycin	27
	Caspase		HER313A (Retina)			149
		Caspase-3	H184A1 (Breast)		Staurosporine	80
	Cysteine protease	Calpain	LNCaP (Prostate), MCF-7, SKBR3 (Breast)		TPA, ionomycin	23
			16 HBE, 1HAEo (Lung/Bronchus)	PMNs transmigration	Toll-like receptor 2 ligands	83
			Caco-2 (Colon), HaCaT (Skin)	Barrier function↓, bacterial translocation	Streptolysin S	82
		Cathepsins (B, S, L)	Mouse pancreatic cancer model	Cell invasion↑		140
Nectin-1α	γ-secretase	Presenilin 1	CHO (Ovary)		TPA	150
Desmoglein 1	Caspase		HaCaT (Skin)		Staurosporine	79
		Caspase-3	A431 (Skin)		UV	141
Desmoglein 2			T84 (Colon)		Camptothecin	14
		Caspase-3	HaCaT cells (Skin), HT29 (Colon)	Cell-cell adhesion↓	Staurosporine	85
	Cysteine protease	Calpain	T84 (Colon)		Camptothecin	14
Desmoglein 3	Caspase		HaCaT (Skin)		Staurosporine	146

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