Niu Jun, Dorahy Douglas J, Gu Xinhua, Scott R J, Draganic Brian, Ahmed Nuzhat, Agrez Michael V
Newcastle Bowel Cancer Research Collaborative, Hunter Medical Research Institute, John Hunter Hospital, The University of Newcastle, Callaghan, New South Wales 2310, Australia.
Int J Cancer. 2002 Jun 1;99(4):529-37. doi: 10.1002/ijc.10397.
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.
我们之前报道过，随着细胞密度增加，αvβ6整合素以蛋白激酶C依赖的方式上调其自身表达。野生型β6整合素亚基也已被证明在体内促进肿瘤生长，其生长增强作用受β6上的丝裂原活化蛋白激酶结合基序和β6亚基特有的11个氨基酸的C末端胞质延伸调节。在此，我们表明11个氨基酸的胞质延伸对于β6表达的细胞密度依赖性增加至关重要，并且11个氨基酸的尾巴对表达αvβ6的结肠癌细胞中细胞密度和PKC介导的β5表达具有显性负效应。表达缺乏11个氨基酸尾巴的β6的细胞对PKC模拟的反应是仅β5亚基的表达增加，这与缺乏组成型αvβ6表达的细胞情况相同。相反，β6上ERK结合位点的缺失分别在存在或不存在11个氨基酸尾巴的情况下，显著损害β6或β5的细胞密度和PKC依赖性表达。我们的研究结果表明，在表达αvβ6的细胞中，存在激酶信号级联的层次结构，并且β6-ERK2相互作用在负责整合素随着细胞汇合而上调的PKC介导的信号通路中占主导地位。鉴于β6-ERK2相互作用在PKC介导的β5和β6整合素亚基表达中占主导地位，靶向β6-ERK2相互作用可能被证明是结肠癌的一种有用的抗癌策略。
