The TSC2/mTOR pathway drives endothelial cell transformation induced by the Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor.
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.
Sodhi
Akrit
A
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chaisuparat
Risa
R
Hu
Jiadi
J
Ramsdell
Amanda K
AK
Manning
Brendan D
BD
Sausville
Edward A
EA
Sawai
Earl T
ET
Molinolo
Alfredo
A
Gutkind
J Silvio
JS
Montaner
Silvia
S
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D042783:Endothelial Cells / Q000473:pathology*; D019288:Herpesvirus 8, Human / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D019899:Paracrine Communication; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D012514:Sarcoma, Kaposi / Q000473:pathology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*
C115448:G protein-coupled receptor, Human herpesvirus 8; D019707:Receptors, Chemokine; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D014764:Viral Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus