title: Differential regulation of cell motility and invasion by FAK.
abstract: Cell migration and invasion are fundamental components of tumor cell metastasis. Increased focal adhesion kinase (FAK) expression and tyrosine phosphorylation are connected with elevated tumorigenesis. Null mutation of FAK results in embryonic lethality, and FAK-/- fibroblasts exhibit cell migration defects in culture. Here we show that viral Src (v-Src) transformation of FAK-/- cells promotes integrin-stimulated motility equal to stable FAK reexpression. However, FAK-/- v-Src cells were not invasive, and FAK reexpression, Tyr-397 phosphorylation, and FAK kinase activity were required for the generation of an invasive cell phenotype. Cell invasion was linked to transient FAK accumulation at lamellipodia, formation of a FAK-Src-p130Cas-Dock180 signaling complex, elevated Rac and c-Jun NH2-terminal kinase activation, and increased matrix metalloproteinase expression and activity. Our studies support a dual role for FAK in promoting cell motility and invasion through the activation of distinct signaling pathways.
authors.affiliation: The Scripps Research Institute, Dept. of Immunology, IMM26, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
authors.forename: Datsun A
authors.initials: DA
authors.lastname: Hsia
authors.forename: Satyajit K
authors.initials: SK
authors.lastname: Mitra
authors.forename: Christof R
authors.initials: CR
authors.lastname: Hauck
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Streblow
authors.forename: Jay A
authors.initials: JA
authors.lastname: Nelson
authors.forename: Dusko
authors.initials: D
authors.lastname: Ilic
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.forename: Erguang
authors.initials: E
authors.lastname: Li
authors.forename: Glen R
authors.initials: GR
authors.lastname: Nemerow
authors.forename: Jay
authors.initials: J
authors.lastname: Leng
authors.forename: Kathryn S R
authors.initials: KS
authors.lastname: Spencer
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
authors.forename: David D
authors.initials: DD
authors.lastname: Schlaepfer
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D048429:Cell Size / Q000235:genetics; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D050719:Crk-Associated Substrate Protein; D004338:Drug Combinations; D005057:Eukaryotic Cells / Q000166:cytology / Q000201:enzymology*; D005353:Fibronectins / Q000378:metabolism / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D007797:Laminin / Q000378:metabolism / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics*; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics; D011506:Proteins; D011509:Proteoglycans / Q000378:metabolism / Q000494:pharmacology; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction / Q000235:genetics; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C493842:Bcar1 protein, mouse; D050719:Crk-Associated Substrate Protein; C099818:DOCK1 protein, human; D004338:Drug Combinations; D005353:Fibronectins; D007797:Laminin; D010750:Phosphoproteins; D011506:Proteins; D011509:Proteoglycans; D011993:Recombinant Fusion Proteins; D050717:Retinoblastoma-Like Protein p130; C059485:matrigel; D003094:Collagen; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src); C496051:Ptk2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D020744:rac GTP-Binding Proteins