Differential regulation of cell motility and invasion by FAK.
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.
Hsia
Datsun A
DA
The Scripps Research Institute, Dept. of Immunology, IMM26, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Mitra
Satyajit K
SK
Hauck
Christof R
CR
Streblow
Daniel N
DN
Nelson
Jay A
JA
Ilic
Dusko
D
Huang
Shuang
S
Li
Erguang
E
Nemerow
Glen R
GR
Leng
Jay
J
Spencer
Kathryn S R
KS
Cheresh
David A
DA
Schlaepfer
David D
DD
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
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