The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor

Akrit Sodhi, Risa Chaisuparat, Jiadi Hu, Amanda K. Ramsdell, Brendan D. Manning, Edward A. Sausville, Earl T. Sawai, Alfredo Molinolo, J. Silvio Gutkind, Silvia Montaner

Research output: Contribution to journalArticle

Abstract

The Kaposi's sarcoma-associated herpesvirus (KSHV), the infectious causative agent of Kaposi's sarcoma (KS), encodes a G protein-coupled receptor (vGPCR) implicated in the initiation of KS. Here we demonstrate that Kaposi's sarcomagenesis involves stimulation of tuberin (TSC2) phosphorylation by vGPCR, promoting the activation of mTOR through both direct and paracrine mechanisms. Pharmacologic inhibition of mTOR with rapamycin prevented vGPCR sarcomagenesis, while overactivation of this pathway was sufficient to render endothelial cells oncogenic. Moreover, mice haploinsufficient for TSC2 are predisposed to vascular sarcomas remarkably similar to KS. Collectively, these results implicate mTOR in KS initiation and suggest that the sarcomagenic potential of KSHV may be a direct consequence of the profound sensitivity of endothelial cells to vGPCR dysregulation of the TSC2/mTOR pathway.

Original languageEnglish (US)
Pages (from-to)133-143
Number of pages11
JournalCancer Cell
Volume10
Issue number2
DOIs
StatePublished - Aug 2006
Externally publishedYes

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Human Herpesvirus 8
Kaposi's Sarcoma
G-Protein-Coupled Receptors
Endothelial Cells
Sirolimus
Sarcoma
Blood Vessels
Phosphorylation

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. / Sodhi, Akrit; Chaisuparat, Risa; Hu, Jiadi; Ramsdell, Amanda K.; Manning, Brendan D.; Sausville, Edward A.; Sawai, Earl T.; Molinolo, Alfredo; Gutkind, J. Silvio; Montaner, Silvia.

In: Cancer Cell, Vol. 10, No. 2, 08.2006, p. 133-143.

Research output: Contribution to journalArticle

Sodhi, A, Chaisuparat, R, Hu, J, Ramsdell, AK, Manning, BD, Sausville, EA, Sawai, ET, Molinolo, A, Gutkind, JS & Montaner, S 2006, 'The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor', Cancer Cell, vol. 10, no. 2, pp. 133-143. https://doi.org/10.1016/j.ccr.2006.05.026
Sodhi, Akrit ; Chaisuparat, Risa ; Hu, Jiadi ; Ramsdell, Amanda K. ; Manning, Brendan D. ; Sausville, Edward A. ; Sawai, Earl T. ; Molinolo, Alfredo ; Gutkind, J. Silvio ; Montaner, Silvia. / The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor. In: Cancer Cell. 2006 ; Vol. 10, No. 2. pp. 133-143.
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