The integrin cytoplasmic-tail motif EKQKVDLSTDC is sufficient to promote tumor cell invasion mediated by matrix metalloproteinase (MMP)-2 or MMP-9.
Integrins promote cellular invasion through a combination of activities, including adhesion to an extracellular matrix ligand, which result in the generation of intracellular signals that lead to changes in cell behavior. Until now, there have been no data that identify a particular region of the cytoplasmic tail of integrin subunits as being responsible specifically for promoting the invasive activity of tumor cells. In this report, we show that amino acids with the sequence EKQKVDLSTDC, which are the C-terminal residues of the integrin beta6 subunit, promote alphavbeta6-dependent invasion in a matrix metalloproteinase (MMP)-9-dependent fashion. This same peptide sequence, when expressed at the cytoplasmic end of the beta3 integrin subunit, was able to enhance alphavbeta3-mediated invasive and enzymatic activity of tumor cells in an MMP-2-dependent fashion. Our results show that these 11 amino acids, when expressed at the C terminus of the beta subunit, are responsible for regulating the activity of invasion-promoting degradative enzymes, whereas the specific MMP involved in this cellular behavior is dependent on the context of the remainder of the beta integrin subunit.
Morgan
Mark R
MR
Tumour Biology Laboratory, Cancer Research UK Clinical Centre, Barts and The London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Sq., London EC1M 6BQ, United Kingdom.
Thomas
Gareth J
GJ
Russell
Alan
A
Hart
Ian R
IR
Marshall
John F
JF
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004338:Drug Combinations; D005109:Extracellular Matrix / Q000378:metabolism; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016023:Integrins / Q000737:chemistry*; D007797:Laminin / Q000378:metabolism; D008024:Ligands; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D019096:Vitronectin / Q000378:metabolism
D000596:Amino Acids; D004338:Drug Combinations; D016023:Integrins; D007797:Laminin; D008024:Ligands; D011509:Proteoglycans; D019096:Vitronectin; C059485:matrigel; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9