Article

Lyle KS, Raaijkmakers JH, Bruinsma W, Bos JL, de Rooij JcAMP-induced Epac-Rap activation inhibits epithelial cell migration by modulating focal adhesion and leading edge dynamics. Cell Signal 20: 1104-1116

Department of Physiological Chemistry, Centre for Biomedical Genetics and Cancer Genomics Centre, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
Cellular Signalling (Impact Factor: 4.32). 07/2008; 20(6):1104-16. DOI: 10.1016/j.cellsig.2008.01.018
Source: PubMed

ABSTRACT

Epithelial cell migration is a complex process crucial for embryonic development, wound healing and tumor metastasis. It depends on alterations in cell-cell adhesion and integrin-extracellular matrix interactions and on actomyosin-driven, polarized leading edge protrusion. The small GTPase Rap is a known regulator of integrins and cadherins that has also been implicated in the regulation of actin and myosin, but a direct role in cell migration has not been investigated. Here, we report that activation of endogenous Rap by cAMP results in an inhibition of HGF- and TGFbeta-induced epithelial cell migration in several model systems, irrespective of the presence of E-cadherin adhesion. We show that Rap activation slows the dynamics of focal adhesions and inhibits polarized membrane protrusion. Importantly, forced integrin activation by antibodies does not mimic these effects of Rap on cell motility, even though it does mimic Rap effects in short-term cell adhesion assays. From these results, we conclude that Rap inhibits epithelial cell migration, by modulating focal adhesion dynamics and leading edge activity. This extends beyond the effect of integrin affinity modulation and argues for an additional function of Rap in controlling the migration machinery of epithelial cells.

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    • "Further studies will investigate this possibility. Previous research has demonstrated that PKA (Howe, 2004) and EPAC (Lyle et al., 2008; Yokoyama et al., 2008; Grandoch et al., 2009; Baljinnyam et al., 2010) can be both positive or negative regulators of cell migration. EPAC also plays a role in cell polarisation and directional cell migration. "

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    • "Further studies will investigate this possibility. Previous research has demonstrated that PKA (Howe, 2004) and EPAC (Lyle et al., 2008; Yokoyama et al., 2008; Grandoch et al., 2009; Baljinnyam et al., 2010) can be both positive or negative regulators of cell migration. EPAC also plays a role in cell polarisation and directional cell migration. "
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    • "The total number and associated area of focal adhesions detected within fixed MDA-MB 231 cells seeded on FN (20 μg/ml) and stained with anti-vinculin antibodies were quantified with ImageJ software using a procedure adapted from a previously described approach [20] [21]. Briefly, center region of cells containing the nucleus and majority of the cell body was manually traced and masked. "
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