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Integrins and cell proliferation

regulation of cyclin-dependent kinases via cytoplasmic signaling pathways

Martin Alexander Schwartz1,* and Richard K. Assoian2

1 Department of Vascular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
2 Department of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104, USA
* Author for correspondence (e-mail: schwartz{at}scripps.edu )



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  		Fig. 1. Integrin/RTK synergies that regulate cell cycle progression. Integrins enhance activation of RTKs by their growth factor (GF) ligands and enhance transmission of the signal to ERK at multiple points. Integrins both directly activate and enhance growth factor activation of Rac and Cdc42 through an effect on membrane targeting. Integrins contribute to activation of PI3K, possibly via FAK and Cdc42, and promote polymerization and organization of actin filaments through both direct physical connections (that are not displayed) and a variety of signaling pathways. Integrin interactions with caveolin and Shc also contribute to cell cycle progression, although whether this is due to Ras/ERK or unknown pathways is unclear. Note that many signaling events such as Raf/MEK/ERK and Akt activation occur on the membrane even though they are drawn in the cytoplasm to avoid overcrowding.

 


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  		Fig. 2. The hierarchy of integrin-specific signals. Integrin {alpha}vß3 selectively associates with and enhances signaling by RTK receptors. It also activates several pathways including NF-{kappa}B, calcium influx and possibly others yet to be identified. Integrins {alpha}vß3, {alpha}5ß1 and {alpha}1 ß1 interact with caveolin and stimulate Shc phosphorylation and possibly other events. Integrins {alpha}vß3 and {alpha}5ß1 also activate PI3K. Integrin {alpha}2ß1 stimulates p38 MAP kinase, which may inhibit cyclin D1 expression in some cells. Most integrins activate FAK and Rho family GTPases on rigid ECMs that resist tension and promote focal adhesion formation. The model is meant to emphasize general trends rather than the absolute specificity of each effect.

 


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  		Fig. 3. Regulation of cyclin D1. A working model depicts the cooperative effects of growth factor receptors and integrins on PI3K, ERK and Rac that regulate cyclin D1 levels. Each of these signaling components has the potential to stimulate the expression of cyclin D1 mRNA. Rac and PI3K are also involved in the translation and stabilization of cyclin D1 protein, respectively.

 




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