alpha(v)beta(6) Integrin expression in diseased and transplanted kidneys.

BACKGROUND: Integrins have been implicated in the pathogenesis of a diverse range of kidney diseases. Herein, we provide the first detailed description of an epithelial restricted integrin, alpha(v)beta(6), in kidney biopsies from patients suffering acute and chronic renal diseases and after transplantation. METHODS: Immunoperoxidase staining for beta(6) was performed on 267 selected biopsy specimens from native (N= 126) and transplanted kidneys (N= 141) and scored semiquantitatively. The site of beta(6) expression in tubules was determined using haematoxylin counterstaining and by colocalization with Tamm-Horsfall protein. Comparisons were made between subcategories of diseases of native kidneys and between "service" and "protocol" biopsies of transplanted kidneys. RESULTS: beta(6), when present, is largely confined to the distal tubules and collecting ducts, colocated with Tamm-Horsfall protein. When sparsely present, it was often restricted to the tubular segment associated with the juxtaglomerular apparatus. It was found in tubular cells shed into the urine. beta(6) was not expressed in thin membrane nephropathy, or in nonproliferative forms of glomerulonephritis, with the exception of focal and segmental glomerulosclerosis (FSGS). It was diffusely expressed where there was glomerular necrosis or thrombosis and in most forms of acute or chronic tubulointerstitial disease. beta(6) was diffusely up-regulated in allografts biopsied for delayed function, in almost all kidneys that have clinical or subclinical rejection episodes and was prominent in chronic allograft nephropathy. CONCLUSION: beta(6) integrin is not normally expressed in adult native or transplanted kidneys but is commonly up-regulated in the distal tubule in disease. Our descriptive study suggests that it is a molecule worthy of further study.

Integrin expression in colon cancer cells is regulated by the cytoplasmic domain of the beta6 integrin subunit.

We have previously reported that the alphavbeta6 integrin upregulates its own expression in a protein kinase C-dependent manner with increasing cell density. The wild-type beta6 integrin subunit has also been shown to promote tumour growth in vivo and its growth-enhancing effect is regulated by both a MAP kinase binding motif on beta6 and the 11 amino acid C-terminal cytoplasmic extension unique to the beta6 subunit. Herein, we show that the 11 amino acid cytoplasmic extension is essential for the cell density-dependent increase in beta6 expression and that the 11 amino acid tail exerts a dominant negative effect on cell density- and PKC-mediated beta5 expression in alphavbeta6-expressing colon cancer cells. Cells that express beta6 lacking the 11 amino acid tail respond to PKC simulation with increased expression of only the beta5 subunit as seen for cells that lack constitutive alphavbeta6 expression. In contrast, loss of the ERK binding site on beta6 markedly impairs cell density- and PKC-dependent expression of either beta6 or beta5 in the presence or absence of the 11 amino acid tail, respectively. Our findings suggest that in alphavbeta6-expressing cells, a hierarchy of kinase signalling cascades exists and that the beta6-ERK2 interaction dominates over PKC-mediated signalling pathways responsible for integrin upregulation with cell confluence. Given the dominance of the beta6-ERK2 interaction over PKC-mediated expression of both beta5 and beta6 integrin subunits, targeting the beta6-ERK2 interaction may prove useful as an anticancer strategy in colon cancer.

Direct integrin alphavbeta6-ERK binding: implications for tumour growth.

Blockade of the mitogen-activated protein (MAP) kinase pathway suppresses growth of colon cancer in vivo. Here we demonstrate a direct link between the extracellular signal-regulated kinase ERK2 and the growth-promoting cell adhesion molecule, integrin alphavbeta6, in colon cancer cells. Down-regulation of beta6 integrin subunit expression inhibits tumour growth in vivo and MAP kinase activity in response to serum stimulation. In alphavbeta6-expressing cells ERK2 is bound only to the beta6 subunit. The increase in cytosolic MAP kinase activity upon epidermal growth factor stimulation is all accounted for by beta6-bound ERK. Deletion of the ERK2 binding site on the beta6 cytoplasmic domain inhibits tumour growth and leads to an association between ERK and the beta5 subunit. The physical interaction between integrin alphavbeta6 and ERK2 defines a novel paradigm of integrin-mediated signalling and provides a therapeutic target for cancer treatment.