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MBC in Press, published online ahead of print October 27, 2004
Mol. Biol. Cell 10.1091/mbc.E04-05-0399

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Submitted on May 14, 2004
Revised on September 25, 2004
Accepted on October 11, 2004

Insulin-like Growth Factor I Controls Adhesion Strength Mediated by {alpha}5{beta}1 Integrins in Motile Carcinoma Cells

Laura Lynch,* Pavel I. Vodyanik,{dagger} David Boettiger, and Marina A. Guvakova{ddagger}

Department of Microbiology, University of Pennsylvania Medical Center, Philadelphia, PA 19104

Monitoring Editor: Carl-Henrik Heldin

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 µdynes/µm2 in cells attached to fibronectin via {alpha}5{beta}1 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 PI-3 kinase inhibitor LY-294002, but is unaffected by MEK 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 {alpha}5{beta}1 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.

Present addresses: *Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104; {dagger}Department of Infectious Disease, Pavlov State Medical School, St. Petersburg, 197086 Russia.

{ddagger}Corresponding author. E-mail: guvakova{at}mail.med.upenn.edu




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