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.
Ahmed
Nuzhat
N
Gynaecological Cancer Research Centre, The Royal Women's Hospital, Melbourne and University of Melbourne, Melbourne, Australia.
Niu
Jun
J
Dorahy
Douglas J
DJ
Gu
Xinhua
X
Andrews
Sarah
S
Meldrum
Cliff J
CJ
Scott
Rodney J
RJ
Baker
Mark S
MS
Macreadie
Ian G
IG
Agrez
Michael V
MV
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm; D001665:Binding Sites / Q000187:drug effects; D002455:Cell Division; D003600:Cytosol / Q000201:enzymology; D016373:DNA, Antisense / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics; D019809:Streptavidin / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D016373:DNA, Antisense; D006133:Growth Substances; D016023:Integrins; D010446:Peptide Fragments; D021122:Protein Subunits; D012333:RNA, Messenger; C073878:integrin alphavbeta6; D019809:Streptavidin; D020928:Mitogen-Activated Protein Kinases