Abstract：
:Kaposi's sarcoma-associated herpes virus (KSHV) contributes to the pathogenesis of Kaposi's sarcoma and primary effusion lymphomas. KSHV encodes a G protein-coupled receptor (KSHV-GPCR) that signals constitutively and transforms NIH3T3 cells. Here, we show that KSHV-GPCR transformation requires activation of the small G protein Rac1 and its effector, the p21-activated kinase 1 (Pak1). Either transient or sustained expression of KSHV-GPCR activated both Rac1 and Pak1. Furthermore, expression of dominant-negative mutants of Rac (RacN17) or Pak1 (PakR299, Pak-PID) inhibited KSHV-GPCR-induced focus formation and growth in soft agar. We also demonstrate that signaling from Pak1 to nuclear factor-kappaB (NFkappaB) is required for cell transformation induced by KSHV-GPCR. KSHV-GPCR induced transcriptional activation by NFkappaB. This process is inhibited by the PAK-PID, whereas reciprocally, expression of constitutively active Pak1 (PakL107F) activated NFkappaB comparably to KSHV-GPCR. The Pak-PID and RacN17 inhibited the KSHV-GPCR-induced phosphorylation of inhibitor of kappaB kinase-beta and inhibitor of kappaB-alpha, implying that it is Pak1-dependent phosphorylation and subsequent destruction of the inhibitor of kappaB proteins that allows NFkappaB activation. Finally, experiments with the KSHV-GPCR inverse agonist interferon-gamma-inducible protein-10, the Galpha(i) inhibitor pertussis toxin, and an inhibitor of phosphatidylinositol 3'-kinase, wortmannin, indicate that signaling through the Galpha(i) pathway and phosphatidylinositol 3'-kinase contributes to the cell transformation and NFkappaB activation induced by the KSHV-GPCR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Dadke D,Fryer BH,Golemis EA,Field Jsubject
Has Abstractpub_date
2003-12-15 00:00:00pages
8837-47issue
24eissn
0008-5472issn
1538-7445journal_volume
63pub_type
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