Signaling of Type II Oncostatin M Receptor

Abstract

Oncostatin M (OSM) mediates its bioactivities through two different heterodimer receptors. They both involve the gp130-transducing receptor, which dimerizes with either leukemia inhibitory receptor ␤ or with OSM receptor ␤ (OSMR␤) to generate, respectively, type I and type II OSM receptors. Co-precipitation of gp130-associated proteins, flow cytometry, polymerase chain reaction, and tyrosine phosphorylation analyses allowed the characterization of both types of OSM receptors expressed on the surface of different cell lines. It also allowed the detection of a large size protein, p250, that specifically associates to the type II OSM receptor components and that is tyrosine-phosphorylated after the activation peak of the gp130⅐OSMR␤ heterocomplex. The restricted expression of type I OSM receptor by the JAR choriocarcinoma cell line, and type II receptor by the A375 melanoma cell line, permitted the characterization of their signaling machineries. Both type I and type II OSM receptors activated Jak1, Jak2, and Tyk2 receptor-associated tyrosine kinases. The information is next relayed to the nucleus by the STAT3 transcriptional activator, which is recruited by both types of OSM receptors. In addition, STAT5b was specifically activated through the gp130⅐OSMR␤ type II heterocomplex.The signaling pathway differences observed between the common type I LIF/OSM receptor and the specific type II OSM receptor might explain some of the bioactivities specifically displayed by OSM.Oncostatin M (OSM) 1 is a multifunctional cytokine belonging to the interleukin-6 (IL-6) family and that shares many properties with those reported for LIF (1). Both OSM and LIF are able to inhibit the spontaneous differentiation of embryonic stem cells (2). They also induce the terminal differentiation of the M1 murine myeloid cell line (3). Like the other IL-6 family members, OSM has been shown to induce acute phase protein synthesis in hepatocytes (4). Beside these LIF-shared bioactivities, OSM displays some specific properties and can inhibit the growth of a variety of solid tumor cells (5) and triggers in vitro the proliferation of Kaposi's sarcoma-derived cell lines (6, 7). In addition, expression of an oncostatin M transgene in the early T cell lineage stimulates a dramatic accumulation of T cells in the mice lymph nodes (8).The redundancy of OSM and LIF biological properties is in part explained by the shared use of a common heterocomplex receptor composed of the gp130 signal transducing protein associated with the LIF receptor ␤ (LIFR␤) component (9, 10). Binding experiments have pointed out the existence of a second and different high affinity receptor for OSM (also referred to as type II OSM receptor) (9 -11). Type II OSM receptor complex binds OSM in a specific manner and is not recognized by LIF (9 -11). Type II receptor also involves a gp130-transducing component that associates with a second receptor subunit very recently isolated as OSM receptor ␤ (OSMR␤), which displays an apparent molecular mass of 180 kDa (12). Comparison of OSMR␤ t...

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

“…Two highly homologous and redundant STAT5 isoforms, STAT5a and STAT5b exist (Buitenhuis et al, 2004) and could be detected in OSRGA cells (Figure 5a, bottom panel). OSM treatment clearly modified the electrophoretic migration of STAT5b, indicating that at least this isoform was activated by OSM as shown previously (Auguste et al, 1997). By immunocytochemistry, we observed a nuclear translocation of STAT5 after 15 min of OSM treatment ( Figure 5b).…”

“…As described previously, binding of OSM to its specific receptor triggers the activation of kinases such as ERK½, Akt and PKCd, and of the transcription factors STAT1, 3 and 5 (Auguste et al, 1997;Chen and Benveniste, 2004;Chipoy et al, 2004). Here, the use of specific kinase inhibitors indicated that the PI3K/Akt and the PKCd pathways have an anti-apoptotic function in osteosarcoma, whereas STAT5 appears necessary for caspase-3 activation and apoptosis.…”

“…Binding of OSM to its receptor complex (gp130-OSMRb) triggers the activation of two main pathways: the JAK-signal transducer and activator of transcription (STAT) (with STAT1, STAT3 and STAT5) and the mitogen-activated protein kinase (with extracellular signal-regulated kinase (ERK)½) signaling pathways (Auguste et al, 1997;Chen and Benveniste, 2004). Like other IL-6 type cytokines, OSM plays a crucial role in inflammation, immune response, hematopoiesis, liver and neuronal regeneration (Kamiya et al, 1999;Chen and Benveniste, 2004).…”

STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

“…12 The OSMR complex activates Janus Kinases 1 and 2 (JAK1 and JAK2), which in turn activate Signal Transducer and Activator of Transcription 3 (STAT3), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)-AKT-mediated signaling cascades. [13][14][15][16][17][18] Elevated levels of OSM in the TME are associated with highly aggressive metastatic cancers, increased risk of tumor recurrence, and a poor prognosis. [19][20][21][22][23][24] In breast cancer, OSM is concentrated at the invasive edges of highly metastatic tumors where cells often display mesenchymal cell characteristics and express the cancer stem cell marker CD44.…”

Two Different Epitopes of the Signal Transducer gp130 Sequentially Cooperate on IL-6-Induced Receptor Activation

“…Studies on the gp130/OSMR heterodimer (42) and more recent investigations on erythropoietin receptor homodimerization (43) suggest that cytokine receptors may appear as preformed dimers on the cell surface. On ligand binding, these receptor dimers switch from an inactive to an active conformation.…”