alpha6beta4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia

Ashton, G H S; Sorelli, Paolo; Mellerio, Jemima E.; Keane, Fergus; Eady, R.A.J.; McGrath, John A.

doi:10.1046/j.1365-2133.2001.04038.x

Cited by 66 publications

(60 citation statements)

References 48 publications

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“…Mice carrying a null mutation of the α6 or β4 subunit do not form HDs and die shortly after birth because of severe blistering of their skin (Dowling et al, 1996;Georges-Labouesse et al, 1996;van der Neut et al, 1996). Similarly, humans who have an autosomal recessive mutation in the genes for either of these integrin subunits exhibit epidermal blistering, the degree of severity depending on the nature of the mutation (Ashton et al, 2001). Because of the perinatal lethality of the α6 and β4 knockout mice, postdevelopmental studies on the effects of the loss of α6β4 were impossible.…”

Section: Discussionmentioning

confidence: 99%

Keratinocytes display normal proliferation, survival and differentiation in conditional β4-integrin knockout mice

Raymond

Kreft

Janssen

et al. 2005

Journal of Cell Science

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distribution of a range of adhesion receptors and basement membrane proteins was unaltered. Moreover, loss of α6β4 did not affect squamous differentiation, proliferation or survival, except for areas in which keratinocytes had detached from the basement membrane. These in vivo observations were confirmed in vitro by using immortalized keratinocytes -derived from β4-subunit conditional knockout mice -from which the gene encoding β4 had been deleted by Cre-mediated recombination. Consistent with the established role of α6β4 in adhesion strengthening, its loss from cells was found to increase their motility. Our findings clearly demonstrate that, after birth, epidermal differentiation, proliferation and survival all proceed normally in the absence of α6β4, provided that cell adhesion is not compromised.

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Section: Discussionmentioning

confidence: 99%

Keratinocytes display normal proliferation, survival and differentiation in conditional β4-integrin knockout mice

Raymond

Kreft

Janssen

et al. 2005

Journal of Cell Science

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“…MEN2A-or MEN2B-inducible genes (type II or type III genes) showed a wide diversity in their possible physiological functions. They include protein kinases (EMK2, PKA-RI), 36,37 cell adhesion molecule (ITGA6), 38,39 microtubule-associated protein (TACC3), 40 protease (neuropsin), 41 and translation initiation factor (EIF4G3). 42 Of 11 type II or type III genes identified, we focused on the STC1 gene because it was reported that it may be involved in the early skeletal development 20 that is affected in MEN 2B patients.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Gene Expression Induced by RET with MEN2A or MEN2B Mutation

Watanabe¹,

Ichihara²,

Hashimoto³

et al. 2002

The American Journal of Pathology

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Germ-line point mutations of the RET gene are responsible for multiple endocrine neoplasia (MEN) type 2A and 2B that develop medullary thyroid carcinoma and pheochromocytoma. We performed a differential display analysis of gene expression using NIH 3T3 cells expressing the RET-MEN2A or RET-MEN2B mutant proteins. As a consequence, we identified 10 genes induced by both mutant proteins and eight genes repressed by them. The inducible genes include cyclin D1, cathepsins B and L, and cofilin genes that are known to be involved in cell growth, tumor progression, and invasion. In contrast, the repressed genes include type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metalloproteinase 3 (TIMP3) genes that have been implicated in tumor suppression. In addition, six RET-MEN2A-and five RET-MEN2B-inducible genes were identified. Among 21 genes induced by RET-MEN2A and/or RET-MEN2B, six genes including cyclin D1, cathepsin B, cofilin, ring finger protein 11 (RNF11), integrin-␣6, and stanniocalcin 1 (STC1) genes were also induced in TGW human neuroblastoma cells in response to glial cell line-derived neurotrophic factor stimulation. Because the STC1 gene was found to be highly induced by both RET-MEN2B and glial cell line-derived neurotrophic factor stimulation, and the expression of its product was detected in medullary thyroid carcinoma with the MEN2B mutation by immunohistochemistry, this may suggest a possible role for STC1 in the development of MEN 2B phenotype. The RET proto-oncogene encodes a receptor tyrosine kinase with a cadherin-related motif and a cysteine-rich domain in the extracellular domain and is located on chromosome 10q11.2.1,2 It has been demonstrated that RET is a functional receptor for four related neurotrophic factors including glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin, and persephin. These factors are known to require glycosylphosphatidylinositol-anchored co-receptors, GFR-␣s, as ligand-binding components and to promote the survival of various central and peripheral neurons in culture.1,2 In addition, gene knockout studies revealed that the GDNF/RET signaling plays a crucial role in the development of the enteric nervous system and the kidney. [3][4][5][6] Germline mutations of the RET gene cause dominant inherited cancer syndromes; multiple endocrine neoplasia (MEN) type 2A and 2B.7-10 MEN 2A is characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia. MEN 2B shows a more complex phenotype with association of MTC, pheochromocytoma, and developmental abnormalities such as mucosal neuroma, hyperganglionosis of the intestinal tract, and marfanoid skeletal changes. The MEN2A mutations were identified in cysteine residues of the RET extracellular domain, leading to ligand-independent RET dimerization. 11,12 The MEN2B mutations were detected in methionine at codon 918 or in alanine at codon 883 in the tyrosine kinase domain and appear to activate RET without dimerization. 12,13 A variety of si...

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“…These mice have an extensive blistering of the skin and other stratified squamous epithelium, and lack hemidesmisome formation (8 -10). In patients with pyloric atresia and junctional epidermolysis bullosa, which manifest as cutaneous blistering, mutations in the integrin ␣ 6 or ␤ 4 gene are present, and the severity of the disease is related to the nature of the mutation (11). Hence, it is believed that a primary function of the integrin ␣ 6 ␤ 4 heterodimer is to anchor the basal epithelial cells to the BMZ.…”

Section: Ucous Membrane Pemphigoid (Mmp)mentioning

confidence: 99%

Identification of an Epitope within Human Integrin α6 Subunit for the Binding of Autoantibody and Its Role in Basement Membrane Separation in Oral Pemphigoid

Rashid

Stern

Ahmed

2006

The Journal of Immunology

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Oral pemphigoid (OP) is a rare chronic autoimmune disease characterized by blisters and erosive lesions in the oral mucosa. We identified an epitope for the binding of OP autoantibodies within the integrin α6 subunit, by cloning four overlapping fragments (A, B, C, and D). Immunoperoxidase studies demonstrated that all of the fragments were present in the oral mucosa. Sera of 20 patients with active OP were studied. All sera bound to integrin α6 in DU145 cell lysate by immunoprecipitation and immunoblot assay. The same sera bound only to fragment A and its subfragment A2 on an immunoblot assay. The specificity of the binding was further characterized by blocking and cross-absorption studies. A 14-aa synthetic peptide A2.1, within fragment A2, bound to all the test sera. The sera in this study bound to only one epitope. Controls were sera samples from 10 healthy volunteers and 40 patients with other variants of mucous membrane pemphigoid and mAb GoH3 and BQ16 to integrin α6. Control sera did not bind to the full-length integrin α6 subunit nor any of the cloned fragments. The OP patient sera and immunoaffinity-purified OP sera, rabbit antisera against fragments A and A2, and mAb GoH3 produced basement membrane separation of oral mucosa in organ culture. This study identifies a peptide within the extracellular domain of integrin α6 molecule, to which Abs in the sera from patients with OP bind, and which may play an important role in the pathogenesis of OP.

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alpha6beta4 integrin abnormalities in junctional epidermolysis bullosa with pyloric atresia

Cited by 66 publications

References 48 publications

Keratinocytes display normal proliferation, survival and differentiation in conditional β4-integrin knockout mice

Keratinocytes display normal proliferation, survival and differentiation in conditional β4-integrin knockout mice

Characterization of Gene Expression Induced by RET with MEN2A or MEN2B Mutation

Identification of an Epitope within Human Integrin α6 Subunit for the Binding of Autoantibody and Its Role in Basement Membrane Separation in Oral Pemphigoid

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