Role of focal adhesion kinase Ser-732 phosphorylation in centrosome function during mitosis.
Focal adhesion kinase (FAK) is the major cytoplasmic tyrosine kinase in focal adhesions and a critical mediator of integrin signaling in a variety of cells, including endothelial cells (ECs). Here we describe a new function for FAK in the regulation of centrosome functions in a Ser-732 phosphorylation-dependent manner during mitosis. Deletion of FAK in primary ECs causes increases in centrosome numbers, multipolar and disorganized spindles, and unaligned chromosomes during mitosis. Re-expression of wild-type FAK, but not S732A mutant, rescued these mitotic defects, suggesting a role for Ser-732 phosphorylation in the regulation of centrosomal functions. Consistent with this possibility, Ser-732-phosphorylated FAK was found to co-localize in centrosomes in mitotic cells. FAK also associated with cytoplasmic dynein in a Ser-732 phosphorylation-dependent manner. Further analysis in FAK-null primary ECs showed that S732A mutant could rescue EC migration but not proliferation or tubulogenesis in vitro. Last, we showed that deletion of FAK in ECs reduced tumor angiogenesis in vivo, which could be restored by re-expression of wild-type FAK but not S732A mutant. Together, these studies demonstrated a novel role for Ser-732 phosphorylation of FAK in the regulation of centrosome function during mitosis, which may contribute to EC proliferation and angiogenesis.
Park
Ann Y J
AY
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Shen
Tang-Long
TL
Chien
Shu
S
Guan
Jun-Lin
JL
D000818:Animals; D002478:Cells, Cultured; D018385:Centrosome / Q000201:enzymology*; D003593:Cytoplasm / Q000201:enzymology; D004398:Dyneins / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010768:Phosphoserine / Q000378:metabolism*; D008941:Spindle Apparatus / Q000201:enzymology
D010768:Phosphoserine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D004398:Dyneins