The basic C-terminal amino acids of calcium-binding protein S100A4 promote metastasis.
The calcium-binding protein S100A4 can induce a metastatic phenotype in animal model systems and its expression in various human cancers has been shown to be associated with metastasis and reduced patient survival. Using a series of nested deletion mutants, it is now shown that the two C-terminal lysine residues are required for the enhanced metastasis, invasion and migration abilities that S100A4 confers on cells in a model system of metastasis. Basic C-terminal residues enhance the affinity between S100A4 and its best characterized target, a recombinant C-terminal fragment of non-muscle myosin II heavy chain isoform A (NMMHC-IIA). In wild-type S100A4 protein, the presence of the C-terminal lysine, residue 101, enhances the rate of association between S100A4 and NMMHC-IIA. These results identify the amino acids of S100A4 that are involved in metastasis induction and show that the C-terminal region of S100A4 is a possible target for inhibitors of its metastatic action.
Ismail
Thamir M
TM
Cancer and Polio Research Fund Laboratories, Biosciences Building, University of Liverpool, Liverpool, UK.
Fernig
David G
DG
Rudland
Philip S
PS
Terry
Carla J
CJ
Wang
Guozheng
G
Barraclough
Roger
R
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement; D006801:Humans; D008239:Lysine / Q000737:chemistry* / Q000378:metabolism*; D020409:Molecular Motor Proteins / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D018995:Myosin Heavy Chains; D008239:Lysine