Formation of extracellular matrix-digesting invadopodia by primary aortic smooth muscle cells.
Invasion of the subendothelial space by vascular smooth muscle cells (VSMCs) contributes to the development and progression of diverse cardiovascular diseases. In this report we show that the expression of activated versions of Src, Cdc42 and Rac1, or a kinase-dead but open form of the p21-activated kinase (PAK1), induces primary rat aorta VSMCs to form extracellular matrix-degrading actin-rich protrusions that are morphologically similar to the invadopodia formed by highly invasive tumor cells. The matrix-degrading structures are enriched in known markers for invadopodia, including cortactin and tyrosine-phosphorylated cortactin and contain the matrix metalloproteinases MMP-9 and MT1-MMP and the urokinase plasminogen activator receptor (uPAR). In contrast to other cell types, invadopodia formation in VSMCs is only weakly supported by the phorbol ester PBDu. Invadopodia formation by Src was dependent on Cdc42, Rac, and ERK, but not on p38 MAPK. Invadopodia formation induced by kinase-dead PAK1 required Src and ERK activity and a direct interaction with the exchange factor PIX. VSMCs embedded in a three-dimensional collagen matrix formed actin- and cortactin-rich extensions that penetrated through holes in the matrix, suggesting that invadopodia-like structures are formed in a three-dimensional environment.
Furmaniak-Kazmierczak
Emilia
E
Department of Biochemistry, Queen's University, Kingston, ON, Canada.
Crawley
Scott W
SW
Carter
Rhonda L
RL
Maurice
Donald H
DH
Côté
Graham P
GP
D000818:Animals; D001011:Aorta / Q000166:cytology*; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000378:metabolism*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051381:Rats; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology
D015240:Phorbol 12,13-Dibutyrate; D003094:Collagen; D019061:src-Family Kinases; C515906:Pak1 protein, rat; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins