Differential activation of the extracellular signal-regulated kinase, Jun Kinase and Janus Kinase-Stat pathways by oncostatin M and basic fibroblast growth factor in AIDS-derived Kaposiʼs sarcoma cells

Abstract

Objectives To determine the integration of signalling pathways associated with two recognized Kaposi's sarcoma (KS) growth factors, oncostatin M (OSM) and basic fibroblast growth factor (bFGF), in the induction of KS cell proliferation. Design and methods We used protein kinase assays, protein-DNA interactions and AP-1 luciferase assays to study the extracellular signal-regulated kinase (FRK), Janus kinase (JAK)-Stat and Jun kinase (JNK) pathways in AIDS-derived KS cells during stimulation with OSM and bFGF. Results Treatment with OSM-induced activation of receptor-associated JAK and phosphorylation of Stat1 and Stat3. Stat1/Stat3 heterodimers interacted with known γ-interferon-activated sites like elements such as the sis-inducible element (SIF) in the c-fos promoter. In contrast, ligation of the bFGF receptor induced Stat3 phosphorylation and its association with the bFGF receptor, but failed to induce JAK activity or protein complexes which interact with GAS-like oligonucleotides. OSM also induced the activation of ERK2 by activating the serine/threonine kinases Raf-1 and [mitogen-activated protein kinase (MAPK) ERK kinase (MEK1)]-1, while bFGF failed to activate any of the above components. Both OSM and bFGF activated the JNK pathway, along with the activation of MEKkinase (MEKK)-1. JNK control the transcriptional activation of c-Jun. Because the above pathways exert an effect on the expression or activation of activation protein (AP)-I components, we confirm that OSM and bFGF induce TPA response element (TRE)-luciferase activity synergistically. Conclusion We demonstrate that OSM and bFGF activate distinct as well as shared signalling cascades in KS cells, which integrate to provide a synergistic AP-1 response by which OSM and bFGF may sustain KS cell growth.