Self-association of calcium-binding protein S100A4 and metastasis.
Elevated levels of the calcium-binding protein S100A4 promote metastasis and in carcinoma cells are associated with reduced survival of cancer patients. S100A4 interacts with target proteins that affect a number of activities associated with metastatic cells. However, it is not known how many of these interactions are required for S100A4-promoted metastasis, thus hampering the design of specific inhibitors of S100A4-induced metastasis. Intracellular S100A4 exists as a homodimer through previously identified, well conserved, predominantly hydrophobic key contacts between the subunits. Here it is shown that mutating just one key residue, phenylalanine 72, to alanine is sufficient to reduce the metastasis-promoting activity of S100A4 to 50% that of the wild type protein, and just 2 or 3 specific mutations reduces the metastasis-promoting activity of S100A4 to less than 20% that of the wild type protein. These mutations inhibit the self-association of S100A4 in vivo and reduce markedly the affinity of S100A4 for at least two of its protein targets, a recombinant fragment of non-muscle myosin heavy chain isoform A, and p53. Inhibition of the self-association of S100 proteins might be a novel means of inhibiting their metastasis-promoting activities.
Ismail
Thamir M
TM
School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, United Kingdom.
Zhang
Shu
S
Fernig
David G
DG
Gross
Stephane
S
Martin-Fernandez
Marisa L
ML
See
Violaine
V
Tozawa
Kaeko
K
Tynan
Christopher J
CJ
Wang
Guozheng
G
Wilkinson
Mark C
MC
Rudland
Philip S
PS
Barraclough
Roger
R
D019943:Amino Acid Substitution; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D055503:Protein Multimerization; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C077591:S100A4 protein, human; D018995:Myosin Heavy Chains