Insulin-like growth factor I controls adhesion strength mediated by alpha5beta1 integrins in motile carcinoma cells.
One of the intriguing questions regarding cell motility concerns the mechanism that makes stationary cells move. Here, we provide the first physical evidence that the onset of breast cancer cell motility in response to insulin-like growth factor I (IGF-I) correlates with lowering of adhesion strength from 2.52 +/- 0.20 to 1.52 +/- 0.13 microdynes/microm2 in cells attached to fibronectin via alpha5beta1 integrin. The adhesion strength depends on the dose of IGF-I and time of IGF-I treatment. Weakening of cell-matrix adhesion is blocked significantly (p < 0.01) by the catalytically inactive IGF-I receptor (IGF-IR) and the phosphoinositide 3-kinase (PI-3 kinase) inhibitor LY-294002, but it is unaffected by mitogen-activated protein kinase kinase inhibitor UO-126 and Src kinase inhibitor PP2. Sustained blockade of Rho-associated kinase (ROCK) with Y-27632 down-regulates adhesion strength in stationary, but not in IGF-I-treated, cells. Jasplakinolide, a drug that prevents actin filament disassembly, counteracts the effect of IGF-I on integrin-mediated cell adhesion. In the absence of growth factor signaling, ROCK supports a strong adhesion via alpha5beta1 integrin, whereas activation of the IGF-IR kinase reduces cell-matrix adhesion through a PI-3K-dependent, but ROCK-independent, mechanism. We propose that disassembly of the actin filaments via PI-3 kinase pathway contributes to weakening of adhesion strength and induction of cell movement. Understanding how cell adhesion and migration are coordinated has an important application in cancer research, developmental biology, and tissue bioengineering.
Lynch
Laura
L
Department of Microbiology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
Vodyanik
Pavel I
PI
Boettiger
David
D
Guvakova
Marina A
MA
D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D002277:Carcinoma / Q000378:metabolism*; D002384:Catalysis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D047630:Depsipeptides / Q000494:pharmacology; D015536:Down-Regulation; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D008858:Microscopy, Phase-Contrast; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases; D019061:src-Family Kinases
D000199:Actins; D000577:Amides; D002070:Butadienes; D000081247:CSK Tyrosine-Protein Kinase; D002867:Chromones; D016895:Culture Media, Serum-Free; D047630:Depsipeptides; D005353:Fibronectins; D007334:Insulin-Like Growth Factor I; D039081:Integrin alpha5beta1; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011725:Pyridines; D011743:Pyrimidines; D020741:rho GTP-Binding Proteins; D054460:rho-Associated Kinases; D019061:src-Family Kinases; C412373:AG 1879; C113580:U 0126; C057531:jasplakinolide; C108830:Y 27632; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000631346:CSK protein, human