WAVE3 promotes cell motility and invasion through the regulation of MMP-1, MMP-3, and MMP-9 expression.
WAVE3 is a member of the WASP/WAVE family of proteins, which play a critical role in the regulation of actin polymerization, cytoskeleton organization, and cell motility. We show here that knockdown of the WAVE3 protein, using RNA interference in MDA-MB-231 cells, decreases phospho-p38 MAPK levels, but not those of phospho-AKT, phospho-ERK, or phospho-JNK. Knockdown of WAVE3 expression also inhibited the expression levels of MMP-1, MMP-3, and MMP-9, but not MMP-2. MMP production could be restored by PMA treatment, without affecting siRNA-mediated WAVE3 knockdown. The WAVE3-mediated downregulation of p38 activity and MMP production is independent of the presence of both WAVE1 and WAVE2, whose expression levels were not affected by loss of WAVE3. We also show that the downstream effect of the WAVE3 knockdown is the inhibition of cell motility and invasion, coupled with increased actin stress fiber formation, as well as reorganization of focal adhesion complexes. These findings suggest that WAVE3 regulates actin cytoskeleton, cell motility, and invasion through the p38 MAPK pathway and MMP production.
Sossey-Alaoui
Khalid
K
Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Khalid.Sossey-Alaoui@roswellPark.org
Ranalli
Tamara A
TA
Li
Xiurong
X
Bakin
Andrei V
AV
Cowell
John K
JK
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D008840:Microfilament Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D051300:Wiskott-Aldrich Syndrome Protein Family; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
D000199:Actins; D007093:Imidazoles; D008840:Microfilament Proteins; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C120153:WASF3 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D048051:p38 Mitogen-Activated Protein Kinases; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D013755:Tetradecanoylphorbol Acetate; C093642:SB 203580