Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin

Phung, Thuy L.; Ziv, Keren; Dabydeen, Donnette; Eyiah-Mensah, Godfred; Riveros, Marcela; Perruzzi, Carole; Sun, Jingfang; Monahan-Earley, Rita A.; Shiojima, Ichiro; Nagy, Janice A.; Lin, Michelle I.; Walsh, Kenneth; Dvorak, Ann M.; Briscoe, David M.; Neeman, Michal; Sessa, William C.; Dvorak, Harold F.; Benjamin, Laura E.

doi:10.1016/j.ccr.2006.07.003

Cited by 398 publications

(394 citation statements)

References 55 publications

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“…Filamin B deficiency exerts effects that resemble those of Shb knockout endothelial cells and in that situation elevated basal Rac1 activity was also observed [20]. In addition, Akt has previously [21] been shown to regulate vascular permeability and thus the junctional rearrangements presently observed in Shb deficient endothelium may additionally be explained by differences in the signaling characteristics of isolated lung endothelial cells with respect to Akt activation. However, a significant component of Akt-dependent VEGF-A stimulated vascular permeability appears to reside in Akt-dependent phosphorylation of eNOS [21].…”

Section: Discussionmentioning

confidence: 89%

“…In addition, Akt has previously [21] been shown to regulate vascular permeability and thus the junctional rearrangements presently observed in Shb deficient endothelium may additionally be explained by differences in the signaling characteristics of isolated lung endothelial cells with respect to Akt activation. However, a significant component of Akt-dependent VEGF-A stimulated vascular permeability appears to reside in Akt-dependent phosphorylation of eNOS [21]. The presently recorded effects of Shb deficiency on endothelial cell signaling characteristics are more pronounced than those previously reported in isolated liver endothelial cells [10], in which reduced responsiveness to VEGF-A was reported for ERK but not for Akt.…”

Section: Discussionmentioning

confidence: 99%

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Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells

Zang

Christoffersson

Tian

et al. 2013

Cellular Signalling

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This is an accepted version of a paper published in Cellular Signalling. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination.Citation for the published paper: Zang, G., Christoffersson, G., Tian, G., Harun-Or-Rashid, M., Vågesjö, E. et al. (2013) "Aberrant association between vascular endothelial growth factor receptor-2 and VEcadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells" Cellular Signalling, 25 (1) Access to the published version may require subscription. NOTICE: this is the author's version of a work that was accepted for publication in Cellular Signalling. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. AbstractVascular permeability is a hallmark response to the main angiogenic factor VEGF-A and we have previously described a reduction of this response in Shb knockout mice.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells

Zang

Christoffersson

Tian

et al. 2013

Cellular Signalling

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“…34,35 Primary mouse lung ECs were isolated from C57Bl/6 mice as described previously. 20 Rapamycin (LC Laboratories) was solubilized in DMSO. Antibodies to total and phosphorylated Akt (p-Akt) (T308 and S473), S6-kinase (T389), S6 ribosomal protein (S235/236) and 4E-BP1 (S65) were from Cell Signaling Technologies; PKCa (S657) antibody was from Santa Cruz Biotechnology; b-actin antibody was from Sigma; and Dylight TM 488-conjugated secondary antibody was from Jackson Immunoresearch Labs.…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

“…19 Rapamycin also has potent antitumor effects and inhibits pathological angiogenesis in cancer. [20][21][22] These important properties have led to the clinical development of rapamycin and related mTOR inhibitors (rapalogs) for the treatment of lymphoma and solid tumors. [23][24][25] As an antiproliferative and antiangiogenic agent, rapamycin is effective in hemangioma.…”

mentioning

confidence: 99%

Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin

Gerald²,

Perruzzi³

et al. 2013

Laboratory Investigation

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Vascular tumors are endothelial cell neoplasms whose cellular and molecular mechanisms, leading to tumor formation, are poorly understood, and current therapies have limited efficacy with significant side effects. We have investigated mechanistic (mammalian) target of rapamycin (mTOR) signaling in benign and malignant vascular tumors, and the effects of mTOR kinase inhibitor as a potential therapy for these lesions. Human vascular tumors (infantile hemangioma and angiosarcoma) were analyzed by immunohistochemical stains and western blot for the phosphorylation of p70 S6-kinase (S6K) and S6 ribosomal protein (S6), which are activated downstream of mTOR complex-1 (mTORC1). To assess the function of S6K, tumor cells with genetic knockdown of S6K were analyzed for cell proliferation and migration. The effects of topical rapamycin, an mTOR inhibitor, on mTORC1 and mTOR complex-2 (mTORC2) activities, as well as on tumor growth and migration, were determined. Vascular tumors showed increased activation of S6K and S6. Genetic knockdown of S6K resulted in reduced tumor cell proliferation and migration. Rapamycin fully inhibited mTORC1 and partially inhibited mTORC2 activities, including the phosphorylation of Akt (serine 473) and PKCa, in vascular tumor cells. Rapamycin significantly reduced vascular tumor growth in vitro and in vivo. As a potential localized therapy for cutaneous vascular tumors, topically applied rapamycin effectively reduced tumor growth with limited systemic drug absorption. These findings reveal the importance of mTOR signaling pathways in benign and malignant vascular tumors. The mTOR pathway is an important therapeutic target in vascular tumors, and topical mTOR inhibitors may provide an alternative and well-tolerated therapy for the treatment of cutaneous vascular lesions.

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“…The PI3 kinase (PI3K)-Akt signaling pathway is involved in various cellular processes including growth, metabolism, reproduction and life span (Gao et al, 2004;Kim et al, 2004;Phung et al, 2006;Stoeltzing et al, 2006). Akt/PKB, a serine/ threonine kinase, is an intermediate signaling component of the PI3K-Akt pathway, and is involved in the transmission of insulin or Ras signaling (Shepherd et al, 1998;Toker and Yoeli-Lerner, 2006).…”

Section: Introductionmentioning

confidence: 99%

Akt is involved in the inhibition of cell proliferation by EGF

Jeon

Jeong²,

Cho³

et al. 2007

Exp Mol Med

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Axin is a negative regulator of the Wnt/β-catenin pathway and is involved in the regulation of axis formation and proliferation. Involvement of Axin in the regulation of other signaling pathways is poorly understood. In this study, we investigated the involvement of Akt in growth regulation by Axin in L929 fibroblasts stimulated by EGF. Akt activity was increased by EGF treatment and Ras activation, respectively. Both the EGFand Ras-induced Akt activations were abolished by Axin induction, as revealed by both Western blot and immunocytochemical analyses. The proliferation and Akt activation induced by EGF were decreased by Axin induction, and the effects of EGF were abolished by treatment of an Akt-specific inhibitor. Therefore, Axin inhibits EGF-induced proliferation of L929 fibroblasts by blocking Akt activation.

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Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin

Cited by 398 publications

References 55 publications

Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells

Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells

Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin

Akt is involved in the inhibition of cell proliferation by EGF

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