A novel interplay between Epac/Rap1 and mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) regulates thrombospondin to control angiogenesis

Doebele, Robert C.; Schulze-Hoepfner, Frank T.; Jiang, Hong; Chlenski, Alexandre; Zeitlin, Benjamin David; Goel, Kushboo; Gomes, Suzana; Liu, Yuru; Abe, Mark K.; Nör, Jacques E.; Lingen, Mark W.; Rosner, Marsha Rich

doi:10.1182/blood-2009-04-217042

Cited by 43 publications

(47 citation statements)

References 44 publications

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“…51 Furthermore, activation of Epac leads to the inhibition of angiogenesis in vivo, an effect partly mimicked by transfection of cells with a CA mutant of Rap1. 52 These studies strongly suggest that dynamic regulation of Rap1 activity is required for EC homeostasis and underscore the importance of identifying regulators and effectors of Rap1 involved in the specific EC response.…”

Section: Discussionmentioning

confidence: 99%

Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin αvβ3

Lakshmikanthan

Sobczak

Chun

et al. 2011

Blood

105

108

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Vascular endothelial growth factor (VEGF) acting through VEGF receptor 2 (VEGFR2) on endothelial cells (ECs) is a key regulator of angiogenesis, a process essential for wound healing and tumor metastasis. Rap1a and Rap1b, 2 highly homologous small G proteins, are both required for angiogenesis in vivo and for normal EC responses to VEGF. Here we sought to determine the mechanism through which Rap1 promotes VEGF-mediated angiogenesis. Using lineage-restricted Rap1-knockout mice we show that Rap1-deficiency in endothelium leads to defective angiogenesis in vivo, in a dose-dependent manner. Using ECs obtained from Rap1-deficient mice we demonstrate that Rap1b promotes VEGF-VEGFR2 kinase activation and regulates integrin activation. Importantly, the Rap1b-dependent VEGF-VEGFR2 activation is in part mediated via integrin α(v)β(3). Furthermore, in an in vivo model of zebrafish angiogenesis, we demonstrate that Rap1b is essential for the sprouting of intersomitic vessels, a process known to be dependent on VEGF signaling. Using 2 distinct pharmacologic VEGFR2 inhibitors we show that Rap1b and VEGFR2 act additively to control angiogenesis in vivo. We conclude that Rap1b promotes VEGF-mediated angiogenesis by promoting VEGFR2 activation in ECs via integrin α(v)β(3). These results provide a novel insight into the role of Rap1 in VEGF signaling in ECs.

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Section: Discussionmentioning

confidence: 99%

Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin αvβ3

Lakshmikanthan

Sobczak

Chun

et al. 2011

Blood

105

108

View full text Add to dashboard Cite

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“…Angiogenesis is a tightly regulated process that is important in development as well as pathologic disease states such as tumor growth and metastasis [19]. In their study, Doebele and colleagues [28] show that pharmacologic activation of Epac with the cAMP analog, 8-pCPT-2′-OMe-cAMP, inhibits vascular-endothelial growth factor (VEGF)-induced angiogenesis in vivo in a matrigel mouse model as well as in a severe combined immunodeficient mouse model of human angiogenesis. It is proposed that Epac/Rap activation induces expression of thrombospondin-1, a key anti-angiogenic molecule, which counteracts VEGF signaling via MEK5/ERK5 (Fig.…”

Section: Others Roles Of Epac In the Vasculaturementioning

confidence: 98%

“…For instance, a recent observation points out a role of Epac in the regulation of angiogenesis [28]. Angiogenesis is a tightly regulated process that is important in development as well as pathologic disease states such as tumor growth and metastasis [19].…”

Section: Others Roles Of Epac In the Vasculaturementioning

confidence: 99%

Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology

Métrich

Berthouze

Morel

et al. 2009

Pflugers Arch - Eur J Physiol

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Exchange proteins directly activated by cyclic AMP (Epac) were discovered 10 years ago as new sensors for the second messenger cyclic AMP (cAMP). Epac family, including Epac1 and Epac2, are guanine nucleotide exchange factors for the Ras-like small GTPases Rap1 and Rap2 and function independently of protein kinase A. Given the importance of cAMP in the cardiovascular system, numerous molecular and cellular studies using specific Epac agonists have analyzed the role and the regulation of Epac proteins in cardiovascular physiology and pathophysiology. The specific functions of Epac proteins may depend upon their microcellular environments as well as their expression and localization. This review discusses recent data showing the involvement of Epac in vascular cell migration, endothelial permeability, and inflammation through specific signaling pathways. In addition, we present evidence that Epac regulates the activity of various cellular compartments of the cardiac myocyte and influences calcium handling and excitation-contraction coupling. The potential role of Epac in cardiovascular disorders such as cardiac hypertrophy and remodeling is also discussed.

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“…The Epac/Rap1-related pathway also appears to be the upstream modulator of Id1 (37). However, Id1 is the canonical and direct downstream effector of the BMP/Smad signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

WSS25 Inhibits Growth of Xenografted Hepatocellular Cancer Cells in Nude Mice by Disrupting Angiogenesis via Blocking Bone Morphogenetic Protein (BMP)/Smad/Id1 Signaling

Qiu

Yang

Pei

et al. 2010

Journal of Biological Chemistry

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Hepatocellular cancer (HCC)3 is the fourth leading cause of death from cancer worldwide and the second most lethal malignant cancer in China since the 1990s (1). However, there are few treatment options aside from surgery (1). HCC is characterized by hypervascularity, which can distinguish HCC from benign lesions by angiography. The strategy of blocking angiogenesis in HCC to inhibit tumor growth has been used for more than 20 years in the clinic (2). However, there are no ideal antiangiogenesis chemotherapeutic agents developed thus far for HCC therapy.Id1 is one of the inhibitors of DNA binding proteins (Ids), which belongs to the basic helix loop helix transcriptional factor superfamily (3). There are four members, Id1, Id2, Id3, and Id4, in the Ids family. Accumulating evidence show that Id1 is overexpressed in solid tumors and their supporting vasculatures (4, 5). Although essential during embryo development, Id1 expression is extremely low in adult tissues, including the quiescent endothelial cells (6). Partial loss of Id1 by genetic manipulation in mice effectively inhibits tumor angiogenesis (6). Id1 ablation leads to the impairment of bone marrow endothelial progenitor cell recruitment and mobilization to form tumor vasculature (7,8). Id1 also has been implicated in the regulation of cell senescence, drug resistance, tumor cell invasion, and apoptosis resistance (9). Interestingly, Id1 has been demonstrated to be highly expressed in malignant HCC and to promote angiogenesis in HCC (10, 11). Thus, Id1 is a rational target for the development of antiangiogenesis therapeutics for HCC.Heparan sulfate proteoglycans are glycoconjugates composed of protein cores to which heparan sulfate (HS) chains are attached. Direct genetic evidence supports that heparan sulfate proteoglycans are necessary for tumor angiogenesis (12). Heparan sulfate proteoglycans, especially those located on the cell surface, act as co-receptors through their HS chains (13). HS chains are negatively charged polymers composed of hexaronic acid and glucosamine disaccharide repeats. Due to their negative charge, they bind multiple functional proteins, including Tables 1 and 2

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A novel interplay between Epac/Rap1 and mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) regulates thrombospondin to control angiogenesis

Cited by 43 publications

References 44 publications

Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin αvβ3

Rap1 promotes VEGFR2 activation and angiogenesis by a mechanism involving integrin αvβ3

Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology

WSS25 Inhibits Growth of Xenografted Hepatocellular Cancer Cells in Nude Mice by Disrupting Angiogenesis via Blocking Bone Morphogenetic Protein (BMP)/Smad/Id1 Signaling

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