JWA as a functional molecule to regulate cancer cells migration via MAPK cascades and F-actin cytoskeleton

Cell Signal. 2007 Jun;19(6):1315-27. doi: 10.1016/j.cellsig.2007.01.007. Epub 2007 Jan 19.

Abstract

Mitogen activated protein kinase (MAPK) cascades are thought to mediate diverse biological functions such as cell growth, differentiation and migration. Activated MAPK may affect microtubule (MT) which is essential for cellular polarity, differentiation and motility. Data in this study show that JWA, a newly identified novel microtubule-associated protein (MAP) was essential for the rearrangement of F-actin cytoskeleton and activation of MAPK cascades induced by arsenic trioxide (As2O3) and phorbol ester (PMA). Over-expression of JWA alone in HeLa, B16 and HCCLM3 cancer cells effectively inhibited cellular migration; whereas, cellular migration was significantly accelerated when cells were deficient in JWA expression. The mechanism underlying these phenomena might be due to JWA affected F-actin rearrangement. Furthermore, JWA deficiency blocked anti-migratory effect produced by As2O3 but enhanced the migratory effect initiated by PMA in HeLa cells. JWA SDR-SLR motifs are not only critical for the MAPK cascades activation, but also for cell migration. Further studies found that JWA differentially regulated cell migration via ERK downstream effectors focal adhesion kinase (FAK) and cyclooxygenase-2 (COX-2). Therefore, JWA regulated-tumor cellular migration might involve MAPK cascades activation and F-actin cytoskeleton rearrangement mechanisms. Our data provide an unexpected role for JWA in tumor cell migration behaviors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Arsenic Trioxide
  • Arsenicals / pharmacology
  • Base Sequence
  • Cell Movement* / drug effects
  • Cyclooxygenase 2 / metabolism
  • Cytoskeleton / drug effects
  • Cytoskeleton / enzymology*
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Focal Adhesion Kinase 1 / metabolism
  • HeLa Cells
  • Heat-Shock Proteins / chemistry
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Kinase 1 / metabolism
  • MAP Kinase Signaling System / drug effects
  • Membrane Transport Proteins
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • Neoplasms / enzymology*
  • Neoplasms / pathology*
  • Oxides / pharmacology
  • Phosphorylation / drug effects
  • Protein Kinase C / metabolism
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • ARL6IP5 protein, human
  • Actins
  • Arsenicals
  • Heat-Shock Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Transport Proteins
  • Oxides
  • Cyclooxygenase 2
  • Focal Adhesion Kinase 1
  • Protein Kinase C
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 1
  • Tetradecanoylphorbol Acetate
  • Arsenic Trioxide