Carcinogenesis Advance Access originally published online on September 10, 2008
Carcinogenesis 2008 29(12):2259-2266; doi:10.1093/carcin/bgn217
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The basic C-terminal amino acids of calcium-binding protein S100A4 promote metastasis
Cancer and Polio Research Fund Laboratories, Biosciences Building, University of Liverpool, Crown Street, Liverpool, L69 7ZB, UK
* To whom correspondence should be addressed. Tel: +44 151 795 4469; Fax: +44 151 795 4406; Email: brb{at}liv.ac.uk
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.
Abbreviations: cDNA, complementary DNA; NMMHC-IIA, non-muscle myosin II heavy chain isoform A; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; rNMMHC-IIA, recombinant C-terminal fragment of non-muscle myosin II heavy chain isoform A; SE, standard error
Received June 16, 2008; revised August 15, 2008; accepted September 6, 2008.