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Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis.

Hood JD, Frausto R, Kiosses WB, Schwartz MA, Cheresh DA - J. Cell Biol. (2003)

Bottom Line: Inhibition of FAK or alphavbeta5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin alphavbeta3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation.The activation of c-Raf by bFGF/alphavbeta3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak.Thus, integrins alphavbeta3 and alphavbeta5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

ABSTRACT
Antagonists of alphavbeta3 and alphavbeta5 disrupt angiogenesis in response to bFGF and VEGF, respectively. Here, we show that these alphav integrins differentially contribute to sustained Ras-extracellular signal-related kinase (Ras-ERK) signaling in blood vessels, a requirement for endothelial cell survival and angiogenesis. Inhibition of FAK or alphavbeta5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin alphavbeta3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation. Furthermore, retroviral delivery of active Ras or c-Raf promoted ERK activity and angiogenesis, which anti-alphavbeta5 blocked upstream of Ras, whereas anti-alphavbeta3 blocked downstream of Ras, but upstream of c-Raf. The activation of c-Raf by bFGF/alphavbeta3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak. Thus, integrins alphavbeta3 and alphavbeta5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.

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bFGF/αvβ3 and VEGF/αvβ5 signaling pathways. A summary of the signaling pathways outlined in this report as it relates to EC cell survival as recently described in Alavi et al. (2003). Evidence presented here reveals that bFGF/αvβ3 and VEGF/αvβ5 differentially activate Ras-Raf-ERK signaling. This, together with our recent work (Alavi et al., 2003), allows us to propose a model whereby each of these signaling pathways accounts for protection of EC from distinct mediators of apoptosis. The αvβ3 pathway promotes an ERK-independent survival mechanism preventing stress-mediated death based on Raf coupling to the mitochondria, whereas the αvβ5 pathway prevents receptor-mediated death in an ERK-dependent manner. In addition, ERK is likely playing a general role in both pathways of angiogenesis because it regulates gene transcription, cell cycle progression, and cell migration, which are critical to the growth and differentiation of new blood vessels.
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fig7: bFGF/αvβ3 and VEGF/αvβ5 signaling pathways. A summary of the signaling pathways outlined in this report as it relates to EC cell survival as recently described in Alavi et al. (2003). Evidence presented here reveals that bFGF/αvβ3 and VEGF/αvβ5 differentially activate Ras-Raf-ERK signaling. This, together with our recent work (Alavi et al., 2003), allows us to propose a model whereby each of these signaling pathways accounts for protection of EC from distinct mediators of apoptosis. The αvβ3 pathway promotes an ERK-independent survival mechanism preventing stress-mediated death based on Raf coupling to the mitochondria, whereas the αvβ5 pathway prevents receptor-mediated death in an ERK-dependent manner. In addition, ERK is likely playing a general role in both pathways of angiogenesis because it regulates gene transcription, cell cycle progression, and cell migration, which are critical to the growth and differentiation of new blood vessels.

Mentions: In this report, evidence is provided that distinct integrin/growth factor receptor pairs differentially activate the Ras-ERK cascade during angiogenesis (Fig. 7). Consistent with earlier reports, blocking αv integrin ligation selectively inhibited the late-acting sustained ERK activity (Fig. 1) that is critical for angiogenesis (Eliceiri et al., 1998), and inhibition of integrin αvβ3 or αvβ5 selectively inhibited bFGF- or VEGF-mediated angiogenesis, respectively (Friedlander et al., 1995). Although αv integrins appear to control sustained/late Ras-ERK signaling, the initial signaling response to these angiogenic growth factors may be supported by preexisting EC integrins such as α2β1 and α1β1, which also contribute to angiogenesis (Senger et al., 2002). In the current work, we found that coordinated signals from integrins αvβ3 or αvβ5 together with bFGF or VEGF, respectively, induce angiogenesis in a manner that is dependent on activation of FAK, Ras, c-Raf, and ERK. However, there was surprising disparity in how these integrin-growth factor pairs activated the Ras-ERK pathway, and thereby likely influence EC survival (Alavi et al., 2003) and angiogenesis (Fig. 7).


Differential alphav integrin-mediated Ras-ERK signaling during two pathways of angiogenesis.

Hood JD, Frausto R, Kiosses WB, Schwartz MA, Cheresh DA - J. Cell Biol. (2003)

bFGF/αvβ3 and VEGF/αvβ5 signaling pathways. A summary of the signaling pathways outlined in this report as it relates to EC cell survival as recently described in Alavi et al. (2003). Evidence presented here reveals that bFGF/αvβ3 and VEGF/αvβ5 differentially activate Ras-Raf-ERK signaling. This, together with our recent work (Alavi et al., 2003), allows us to propose a model whereby each of these signaling pathways accounts for protection of EC from distinct mediators of apoptosis. The αvβ3 pathway promotes an ERK-independent survival mechanism preventing stress-mediated death based on Raf coupling to the mitochondria, whereas the αvβ5 pathway prevents receptor-mediated death in an ERK-dependent manner. In addition, ERK is likely playing a general role in both pathways of angiogenesis because it regulates gene transcription, cell cycle progression, and cell migration, which are critical to the growth and differentiation of new blood vessels.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172815&req=5

fig7: bFGF/αvβ3 and VEGF/αvβ5 signaling pathways. A summary of the signaling pathways outlined in this report as it relates to EC cell survival as recently described in Alavi et al. (2003). Evidence presented here reveals that bFGF/αvβ3 and VEGF/αvβ5 differentially activate Ras-Raf-ERK signaling. This, together with our recent work (Alavi et al., 2003), allows us to propose a model whereby each of these signaling pathways accounts for protection of EC from distinct mediators of apoptosis. The αvβ3 pathway promotes an ERK-independent survival mechanism preventing stress-mediated death based on Raf coupling to the mitochondria, whereas the αvβ5 pathway prevents receptor-mediated death in an ERK-dependent manner. In addition, ERK is likely playing a general role in both pathways of angiogenesis because it regulates gene transcription, cell cycle progression, and cell migration, which are critical to the growth and differentiation of new blood vessels.
Mentions: In this report, evidence is provided that distinct integrin/growth factor receptor pairs differentially activate the Ras-ERK cascade during angiogenesis (Fig. 7). Consistent with earlier reports, blocking αv integrin ligation selectively inhibited the late-acting sustained ERK activity (Fig. 1) that is critical for angiogenesis (Eliceiri et al., 1998), and inhibition of integrin αvβ3 or αvβ5 selectively inhibited bFGF- or VEGF-mediated angiogenesis, respectively (Friedlander et al., 1995). Although αv integrins appear to control sustained/late Ras-ERK signaling, the initial signaling response to these angiogenic growth factors may be supported by preexisting EC integrins such as α2β1 and α1β1, which also contribute to angiogenesis (Senger et al., 2002). In the current work, we found that coordinated signals from integrins αvβ3 or αvβ5 together with bFGF or VEGF, respectively, induce angiogenesis in a manner that is dependent on activation of FAK, Ras, c-Raf, and ERK. However, there was surprising disparity in how these integrin-growth factor pairs activated the Ras-ERK pathway, and thereby likely influence EC survival (Alavi et al., 2003) and angiogenesis (Fig. 7).

Bottom Line: Inhibition of FAK or alphavbeta5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin alphavbeta3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation.The activation of c-Raf by bFGF/alphavbeta3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak.Thus, integrins alphavbeta3 and alphavbeta5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

ABSTRACT
Antagonists of alphavbeta3 and alphavbeta5 disrupt angiogenesis in response to bFGF and VEGF, respectively. Here, we show that these alphav integrins differentially contribute to sustained Ras-extracellular signal-related kinase (Ras-ERK) signaling in blood vessels, a requirement for endothelial cell survival and angiogenesis. Inhibition of FAK or alphavbeta5 disrupted VEGF-mediated Ras and c-Raf activity on the chick chorioallantoic membrane, whereas blockade of FAK or integrin alphavbeta3 had no effect on bFGF-mediated Ras activity, but did suppress c-Raf activation. Furthermore, retroviral delivery of active Ras or c-Raf promoted ERK activity and angiogenesis, which anti-alphavbeta5 blocked upstream of Ras, whereas anti-alphavbeta3 blocked downstream of Ras, but upstream of c-Raf. The activation of c-Raf by bFGF/alphavbeta3 not only depended on FAK, but also required p21-activated kinase-dependent phosphorylation of serine 338 on c-Raf, whereas VEGF-mediated c-Raf phosphorylation/activation depended on Src, but not Pak. Thus, integrins alphavbeta3 and alphavbeta5 differentially regulate the Ras-ERK pathway, accounting for distinct vascular responses during two pathways of angiogenesis.

Show MeSH
Related in: MedlinePlus