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 KAPOSIS-SARCOMA CELLS

Objectives: To determine the integration of signalling pathways associ ated with two recognized Kaposi's sarcoma (KS) growth factors, oncosta tin M (OSM) and basic fibroblast growth factor (bFGF), in the inductio n 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 (ERK), janus kinase (JAK)-St at and Jun kinase (JNK) pathways in AIDS-derived KS cells during stimu lation with OSM and bFGF. Results: Treatment with OSM-induced activati on of receptor-associated JAK and phosphorylation of Stat1 and Stat3. Stat1/Stat3 heterodimers interacted with known gamma-interferon-activa ted sites like elements such as the sis-inducible element (SIE) in the c-fos promoter. In contrast, ligation of the bFGF receptor induced St at3 phosphorylation and its association with the bFGF receptor, but fa iled to induce IAK activity or protein complexes which interact with G AS-like oligonucleotides. OSM also induced the activation of ERK2 by a ctivating the serine/threonine kinases Raf-1 and [mitogen-activated pr otein kinase (MAPK) ERK kinase (MEK1)]-1, while bFGF failed to activat e any of the above components. Both OSM and bFGF activated the JNK pat hway, 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)-1 components, we confirm that OSM and bFGF induce TPA response element (TRE)-luciferase activity synergistically. Conclusion We demonstrate t hat OSM and bFGF activate distinct as well as shared signalling cascad es in KS cells, which integrate to provide a synergistic AP-1 response by which OSM and bFGF may sustain KS cell growth.