Tyrosine Phosphorylation of the β4 Integrin Cytoplasmic Domain Mediates Shc Signaling to Extracellular Signal-regulated Kinase and Antagonizes Formation of Hemidesmosomes

Dans, Michael; Gagnoux‐Palacios, Laurent; Blaikie, Pamela; Klein, Sharon; Mariotti, Agnese; Giancotti, Filippo G.

doi:10.1074/jbc.m008663200

Cited by 129 publications

(132 citation statements)

References 42 publications

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“…This conclusion stands in clear contrast to prior studies indicating that TAM-mutant ␤ 4 localizes efficiently to endogenous HDlike adhesions of 804G cells and that it promotes assembly of HD-like adhesions in (immortalized) PA-JEB keratinocytes (22,23), thus indicated that ␤ 4 TAM is dispensable for HD formation (22).…”

Section: Discussioncontrasting

confidence: 54%

“…The origin and nature of this variant form remain to be established. We have observed that this variant form of ␤ 4 and a canonical form carrying phenylalanine substitutions at Tyr-1422 or Tyr-1440 are both normally incorporated in the HD-like adhesions of 804G cells (23). However, a mutant ␤ 4 carrying both modifications is not, as shown previously (18).…”

mentioning

confidence: 47%

“…3, panel D) and in ␤ 4 Y1422F/Y1440F keratinocytes (panel F). phenylalanine substitutions at Tyr-1422 and Tyr-1440 (23). These more recent findings suggest the alternative hypothesis that the hydroxyl groups of Tyr-1422 and Tyr-1440 may be necessary for interaction with HD components such as, for instance, BP180 (22).…”

Section: Discussionmentioning

confidence: 88%

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Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

Dellambra¹,

Prislei²,

Salvati³

et al. 2001

Journal of Biological Chemistry

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The cytoplasmic domain of ␤ 4 integrin contains two pairs of fibronectin-like repeats separated by a connecting segment. The connecting segment harbors a putative tyrosine activation motif in which tyrosines 1422 and 1440 are phosphorylated in response to ␣ 6 ␤ 4 binding to laminin-5. Primary ␤ 4 -null keratinocytes, obtained from a newborn suffering from lethal junctional epidermolysis bullosa, were stably transduced with retroviruses carrying a full-length ␤ 4 cDNA or a ␤ 4 cDNA with phenylalanine substitutions at Tyr-1422 and Tyr-1440. Hemidesmosome assembly was evaluated on organotypic skin cultures. ␤ 4 -corrected keratinocytes were indistinguishable from normal cells in terms of ␣ 6 ␤ 4 expression, the localization of hemidesmosome components, and hemidesmosome structure and density, suggesting full genetic and functional correction of ␤ 4 -null keratinocytes. In cultures generated from ␤ 4 Y1422F/Y1440Fkeratinocytes, ␤ 4 mutants as well as ␣ 6 integrin, HD1/ plectin, and BP180 were not concentrated at the dermalepidermal junction. Furthermore, the number of hemidesmosomes was strikingly reduced as compared with ␤ 4 -corrected keratinocytes. The rare hemidesmosomes detected in ␤ 4 Y1422F/Y1440F cells were devoid of subbasal dense plates and of inner cytoplasmic plaques with keratin filament insertion. Collectively, our data demonstrate that the ␤ 4 tyrosine activation motif is not required for the localization of ␣ 6 ␤ 4 at the keratinocyte plasma membrane but is essential for optimal assembly of bona fide hemidesmosomes.Human epidermis consists of a stratified squamous epithelium composed of keratinocytes organized in distinct cellular layers. Keratinocytes forming the basal layer firmly adhere to the basement membrane by means of hemidesmosomes (HDs), 1 multiprotein complexes linking the epithelial intermediate filament network to the dermal anchoring fibrils (see Refs. 1 and 2 for review). HDs are formed by the clustering of several cytoplasmic and trans-membrane proteins (2). The cytoplasmic HD plaque components, which include HD1/plectin (3) and the bullous pemphigoid antigen 1 (BP230) (4), act as linkers for elements of the cytoskeleton at the cytoplasmic surface of plasma membrane. The trans-membrane constituents of HDs, which include the ␣ 6 ␤ 4 integrin (5, 6) and the bullous pemphigoid antigen 2 (BP180) (7), serve as cell receptors connecting the cell interior to extracellular matrix proteins.In particular, the ␣ 6 ␤ 4 integrin is a receptor for the basement membrane component laminin-5, a heterotrimeric protein composed of three distinct polypeptides, ␣3, ␤3, and ␥2, which are encoded by three different genes known as LAMA3, LAMB3, and LAMC2, respectively (see Ref. 8 for review). Laminin-5 binds to the basal keratinocyte cell surface through the ␣ 6 ␤ 4 integrin and tightens the dermal-epidermal junction by binding also to the N-terminal NC-1 domain of type VII collagen (9). The crucial importance of the interaction between laminin-5 and its ␣ 6 ␤ 4 receptor in maintaining the integrity of the i...

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Section: Discussioncontrasting

confidence: 54%

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confidence: 47%

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Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

Dellambra¹,

Prislei²,

Salvati³

et al. 2001

Journal of Biological Chemistry

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“…The adaptor protein Shc, recently shown to participate in FAK-independent signaling from antibody-ligated ␤ 4 integrin to ERK (37) and from Met receptor tyrosine kinase-activated ␤ 4 integrin to Ras-and PI3K-dependent pathways (20,38), seemed not to be involved in the ␤ 4 -mCLCA1-mediated signaling in our tumor model. Anti-␤ 4 , anti-HA, and anti-Grb2 immunoprecipitates prepared from FAK-HA-transfected B16-F10 cells bound to mCLCA1 failed to co-precipitate and activate Shc B16-F10 co-transfected with GFP/wtFAK and GFP/FRNK were seeded onto monolayers of BAEC that constitutively express bCLCA2 shown to mediate strong B16-F10 adhesion (5,6).…”

Section: Discussionmentioning

confidence: 85%

Focal Adhesion Kinase Activated by β4 Integrin Ligation to mCLCA1 Mediates Early Metastatic Growth

Abdel-Ghany

Cheng

Elble

et al. 2002

Journal of Biological Chemistry

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Hematogenous metastases originate from tumor cells arrested in the vasculature of select target organs. This arrest is tumor-and tissue-specific and is mediated at least in part by distinct tumor cell/endothelial cell adhesion ligand/receptor pairs (reviewed in Refs. 1 and 2). Studies in our laboratory have shown that lung metastatic human breast cancer cells colonized the lungs following adhesion to hCLCA2, a Ca 2ϩ -sensitive chloride channel protein that is expressed on the endothelial cell luminal surface of human pulmonary arteries, arterioles, and interlobular venules (3). Similar to the unique adhesion functions of other channel proteins (reviewed in Ref. 4), CLCA proteins mediate adhesion via the ␤ 4 integrin tumor cell ligand, which for the first time has been associated with a cell-cell adhesion function (3, 4). This novel adhesion interaction between members of CLCA family of proteins (e.g. bCLCA2 (Lu-ECAM-1), hCLCA2) and the ␤ 4 integrin has been scrutinized by a variety of stringently controlled biochemical and functional assay procedures (3, 5, 6). These assays included (i) the co-immunoprecipitation of the ␤ 4 -hCLCA2 complex from extracts of lung metastatic MDA-MB-231 breast cancer cells bound to monolayers of hCLCA2-transfected human embryonic kidney (HEK) 1 293 cells (3); (ii) the selective binding of immunopurified, recombinant hCLCA2 to membrane-immobilized, reconstituted ␤ 4 integrin in Far Westerns (3); (iii) the increased expression of the ␤ 4 integrin in breast cancer cell lines selected in vivo for enhanced lung colonization and the concomitant increased adhesion of the selected cells to hCLCA2 (3); (iv) the loss of hCLCA2 adhesion of breast cancer cells subjected to selective cleavage of the ␤ 4 integrin with the metalloproteinase matrilysin (3, 7) or tumor cells transfected with mutant ␤ 4 integrin (tail-less) (3); (v) the inhibition of pulmonary metastases by ␤ 4 -hCLCA2 adhesion-blocking antibodies directed against either of the interacting adhesion molecules (3, 5, 6); and (vi) the increased lung metastatic performance of tumor cells overexpressing the ␤ 4 integrin (3). These data are in agreement with previous reports showing that overexpression of the ␤ 4 integrin is associated with an aggressive/metastatic cancer phenotype in several malignancies (reviewed in Ref. 8) and, more recently, with the finding that selection for enhanced lung colonization concurs with prominent overexpression of the ␤ 4 integrin gene in a murine metastasis model analyzed by cDNA microarray (9).Here, B16-F10 melanoma cells, characterized by strong surface expression of the ␤ 4 integrin (10, 11) and consistently high lung colonization potential (12), were employed to explore whether the ␤ 4 integrin interacts with a murine CLCA family member to promote metastasis of mouse lungs. Although the existence of a murine counterpart of hCLCA2 has been suspected by the positive immunohistochemical staining of endothelia of mouse pulmonary blood vessels with anti-bCLCA2 mAb6D3 and by the anti-metastatic effect of ...

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“…Assembly of hemidesmosomes depends on both ␤4 TAM motif and its membrane proximal portion (Gap). 56 LMP2A-mediated modulation of B-cell receptor signaling was affected by mutations in either of the 2 tyrosine residues alone of the LMP2A ITAM motif, while only mutations in both sites restored the hTERT promoter activity. This suggests another distinct difference of LMP2A regulation in epithelial cells in contrast to B-cells.…”

Section: Discussionmentioning

confidence: 99%

Epstein‐Barr virus latent membrane 2A (LMP2A) down‐regulates telomerase reverse transcriptase (hTERT) in epithelial cell lines

Liu

et al. 2004

Intl Journal of Cancer

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The latent membrane protein (LMP) 2A, one of the membranespanning polypeptides encoded by the Epstein-Barr virus (EBV), has been implicated in the maintenance of viral latency and appears to function in part by inhibiting B-cell receptor (BCR) signaling through its ITAM motifs. It has also been suggested that LMP2A is involved in tumorigenesis mediated by EBV. In our study, we determined regulatory effects of LMP2A on the telomerase reverse transcriptase (hTERT) expression. We observed a significant and constant reduction of hTERT mRNA accompanied by decreased telomerase activity in epithelial cells expressing LMP2A. It was further shown that LMP2A inhibited the hTERT promoter activity in transient transfections of both B cells and epithelial cells, and that the ITAM motif was required for this inhibition. Thus LMP2A expression leads to the transcriptional repression of the hTERT gene through specific pathways, which may thereby contribute to the control of EBV-latency.

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Tyrosine Phosphorylation of the β4 Integrin Cytoplasmic Domain Mediates Shc Signaling to Extracellular Signal-regulated Kinase and Antagonizes Formation of Hemidesmosomes

Abstract: Ligation of the ␣ 6 ␤ 4 integrin induces tyrosine phosphorylation of the ␤ 4 cytoplasmic domain, followed by recruitment of the adaptor protein Shc

Cited by 129 publications

References 42 publications

Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

Focal Adhesion Kinase Activated by β4 Integrin Ligation to mCLCA1 Mediates Early Metastatic Growth

Epstein‐Barr virus latent membrane 2A (LMP2A) down‐regulates telomerase reverse transcriptase (hTERT) in epithelial cell lines

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