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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: 4.47). 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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    ABSTRACT: Angiogenesis is an essential process during tissue regeneration; however, the amount of angiogenesis directly correlates with the level of wound scarring. Angiogenesis is lower in scar-free fetal wounds while angiogenesis is raised and abnormal in pathophysiological scarring such as hypertrophic scars and keloids. Delineating the mechanisms that modulate angiogenesis and could reduce scarring would be clinically useful. Beta-adrenoceptors (β-AR) are G protein-coupled receptors expressed on all skin cell-types. They play a role in wound repair but their specific role in angiogenesis is unknown. In this study, a range of in vitro assays (single cell migration, scratch wound healing, ELISAs for angiogenic growth factors and tubule formation) were performed with human dermal microvascular endothelial cells (HDMEC) to investigate and dissect mechanisms underpinning β-AR-mediated modulation of angiogenesis in chick chorioallantoic membranes (CAM) and murine excisional skin wounds. β-AR activation reduced HDMEC migration via cAMP-dependent and PKA-independent mechanisms as demonstrated through use of an EPAC agonist that auto-inhibited the cAMP-mediated β-AR transduced reduction in HDMEC motility; a PKA inhibitor was, conversely, ineffective. ELISA studies demonstrated that β-AR activation reduced pro-angiogenic growth factor secretion from HDMECs (fibroblast growth factor 2) and keratinocytes (vascular endothelial growth factor A) revealing possible β-AR-mediated autocrine and paracrine anti-angiogenic mechanisms. In more complex environments, β-AR activation delayed HDMEC tubule formation and decreased angiogenesis both in the CAM assay and in murine excisional skin wounds in vivo. β-AR activation reduced HDMEC function in vitro and angiogenesis in vivo; therefore, β-AR agonists could be promising anti-angiogenic modulators in skin. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
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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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    • "A number of studies have reported seemingly contradictory results on the role of Rap1 in the regulation of cell migration. Indeed, it has been shown that either increased or decreased activity of Rap1 promotes cell motility (Ahmed et al., 2012; Freeman et al., 2010; Kim et al., 2012; Lyle et al., 2008; McSherry et al., 2011; Ohba et al., 2001; Yajnik et al., 2003; Zheng et al., 2009). Moreover, in cancer cells, both overactivation and inactivation of Rap1 have been associated with increased metastasis. "
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