Oncostatin-M stimulates tyrosine protein phosphorylation in parallel with the activation of p42MAPK/ERK-2 in Kaposi's cells. Evidence that this pathway is important in Kaposi cell growth.

Abstract

Oncostatin-M (OSM) is a potent mitogen for Kaposi's sarcoma (KS) cells. We studied signaling by the OSM receptor in three AIDS-related KS lines and show induction of tyrosine phosphorylation of 145-, 120-, 85-, and 42-kD substrates. The 42-kD substrate was identified as p42MAPK (mitogen-activated protein kinase), also known as ERK-2. This serine/threonine kinase relays mitogenic signals from receptor tyrosine protein kinases (TPKs) or receptor-associated TPKs to transcriptional activators. The OSM dose dependence for MAP kinase activation and induction of KS cell growth were almost identical, suggesting functional linkage. MAP kinase activation was dependent on tyrosine phosphorylation, and both OSM-induced MAP kinase activity and KS cell growth could be suppressed by TPK inhibitors, genistein and geldanomycin. OSM also stimulated tyrosine phosphorylation of similar substrates and MAP kinase activity in human vein endothelial cells. While it has been proposed that the OSM receptor may include the gpl30 subunit of the IL-6 receptor and a-chain of leukemia inhibitory factor (LIF) receptor, neither LIF nor r.IL-6 induced tyrosine protein phosphorylation or p42MI'K activation in KS cells.However, r.IL-6 did stimulate tyrosine phosphorylation and p42'PK activity in the human B cell line, AF-10, while OSM and LIF exerted no effects. Our results indicate that, although the OSM and IL-6 receptors share a common signaling pathway, this pathway is selectively activated by OSM in Kaposi's cells. (J. Clin. Invest. 1993. 92:848-857.)

Oncostatin M Stimulates the Growth of Dermal Fibroblasts Via a Mitogen-Activated Protein Kinase-Dependent Pathway

“…This suggests that endogenous IL-6 synthesis is not directly involved in the OSM-induced mitogenic response of dermal fibroblasts. OSM belongs to a family of cytokines that utilize the Janus kinase (JAK)-STAT signaling pathway (40) and MAP kinase pathway (34). Indeed, it has been reported recently that OSM activates STAT1 and STAT3 in human dermal fibroblasts (21,41).…”

“…It was reported that OSM stimulated tyrosine phosphorylation in various types of cells (34). Therefore, we investigated the effects of tyrosine kinase inhibitor on OSM-induced dermal fibroblast DNA synthesis.…”

Oncostatin M Stimulates Transcription of the Human α2(I) Collagen Gene via the Sp1/Sp3-binding Site

“…OSM belongs to a family of cytokines that utilize the JAK-STAT signaling pathway (10), but OSM activation of other signaling pathways such as mitogen-activated protein kinase has also been observed (35). Indeed, it has been reported recently that OSM stimulates the MMP-1 (interstitial collagen- 1-7) or the mutant probe (same promoter fragment containing a substitution mutation in the proximal TCC motif between bp Ϫ128 and Ϫ126; see ase) gene through AP-1 and STAT response elements that act synergistically (27).…”

Oncostatin M is a proinflammatory mediator. In vivo effects correlate with endothelial cell expression of inflammatory cytokines and adhesion molecules.

“…This is a 10-to 20-fold greater expression of these receptors compared to other cell types (9,10), and is especially significant when compared to the estimated 650 TNF receptors expressed by endothelial cells (2,9). Second, endothelial cells respond to oncostatin M with activation of MAP kinase activity (11), IL-6 secretion (9), and delayed, but prolonged, P-selectin synthesis (12). Third, oncostatin M is the major autocrine growth factor for Kaposi's sarcoma cells (13), and these spindle-shaped cells are thought to be of endothelial cell origin (14,15).…”