Spatial coordination of actin polymerization and ILK-Akt2 activity during endothelial cell migration.
Eukaryotic cell migration proceeds by cycles of protrusion, adhesion, and contraction, regulated by actin polymerization, focal adhesion assembly, and matrix degradation. However, mechanisms coordinating these processes remain largely unknown. Here, we show that local regulation of thymosin-beta4 (Tbeta4) binding to actin monomer (G-actin) coordinates actin polymerization with metalloproteinase synthesis to promote endothelial cell motility. In particular and quite unexpectedly, FRET analysis reveals diminished interaction between Tbeta4 and G-actin at the cell leading edge despite their colocalization there. Profilin-dependent dissociation of G-actin-Tbeta4 complexes simultaneously liberates actin for filament assembly and facilitates Tbeta4 binding to integrin-linked kinase (ILK) in the lamellipodia. Tbeta4-ILK complexes then recruit and activate Akt2, resulting in matrix metalloproteinase-2 production. Thus, the actin-Tbeta4 complex constitutes a latent coordinating center for cell migratory behavior, allowing profilin to initiate a cascade of events at the leading edge that couples actin polymerization to matrix degradation.
Fan
Yi
Y
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Gong
Yanqing
Y
Ghosh
Prabar K
PK
Graham
Linda M
LM
Fox
Paul L
PL
D000199:Actins / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000166:cytology*; D002417:Cattle; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism; D013947:Thymosin / Q000378:metabolism; D000099201:Thymosin beta(4); D000099200:Scaffold Protein ILK
D000199:Actins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D013947:Thymosin; D000099201:Thymosin beta(4); D000099200:Scaffold Protein ILK