title: S100P dissociates myosin IIA filaments and focal adhesion sites to reduce cell adhesion and enhance cell migration.
abstract: S100 proteins promote cancer cell migration and metastasis. To investigate their roles in the process of migration we have constructed inducible systems for S100P in rat mammary and human HeLa cells that show a linear relationship between its intracellular levels and cell migration. S100P, like S100A4, differentially interacts with the isoforms of nonmuscle myosin II (NMIIA, K(d) = 0.5 μM; IIB, K(d) = 8 μM; IIC, K(d) = 1.0 μM). Accordingly, S100P dissociates NMIIA and IIC filaments but not IIB in vitro. NMIIA knockdown increases migration in non-induced cells and there is no further increase upon induction of S100P, whereas NMIIB knockdown reduces cell migration whether or not S100P is induced. NMIIC knockdown does not affect S100P-enhanced cell migration. Further study shows that NMIIA physically interacts with S100P in living cells. In the cytoplasm, S100P occurs in discrete nodules along NMIIA-containing filaments. Induction of S100P causes more peripheral distribution of NMIIA filaments. This change is paralleled by a significant drop in vinculin-containing, actin-terminating focal adhesion sites (FAS) per cell. The induction of S100P, consequently, causes significant reduction in cellular adhesion. Addition of a focal adhesion kinase (FAK) inhibitor reduces disassembly of FAS and thereby suppresses S100P-enhanced cell migration. In conclusion, this work has demonstrated a mechanism whereby the S100P-induced dissociation of NMIIA filaments leads to a weakening of FAS, reduced cell adhesion, and enhanced cell migration, the first major step in the metastatic cascade.
authors.affiliation: Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, United Kingdom.
authors.forename: Min
authors.initials: M
authors.lastname: Du
authors.forename: Guozheng
authors.initials: G
authors.lastname: Wang
authors.forename: Thamir M
authors.initials: TM
authors.lastname: Ismail
authors.forename: Stephane
authors.initials: S
authors.lastname: Gross
authors.forename: David G
authors.initials: DG
authors.lastname: Fernig
authors.forename: Roger
authors.initials: R
authors.lastname: Barraclough
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rudland
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004318:Doxycycline / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D024507:Nonmuscle Myosin Type IIA / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: D002135:Calcium-Binding Proteins; D009363:Neoplasm Proteins; C103003:S100P protein, human; D049452:Green Fluorescent Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D024507:Nonmuscle Myosin Type IIA; D004318:Doxycycline