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.
Niu
Jun
J
Newcastle Bowel Cancer Research Collaborative, Hunter Medical Research Institute, John Hunter Hospital, The University of Newcastle, Callaghan, New South Wales 2310, Australia.
Dorahy
Douglas J
DJ
Gu
Xinhua
X
Scott
R J
RJ
Draganic
Brian
B
Ahmed
Nuzhat
N
Agrez
Michael V
MV
D020816:Amino Acid Motifs; D001665:Binding Sites; D015153:Blotting, Western; D002448:Cell Adhesion; D002469:Cell Separation; D003110:Colonic Neoplasms / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039641:Integrin beta Chains; D016023:Integrins / Q000096:biosynthesis* / Q000737:chemistry*; D011233:Precipitin Tests; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014407:Tumor Cells, Cultured
D039641:Integrin beta Chains; D016023:Integrins; C072170:integrin beta6; D011493:Protein Kinase C