Signal transduction pathways which mediate reverse signaling through CD137 ligand have been studied using M-CSF or RANK ligand-induced osteoclast differentiation of murine bone marrow cells. The CD137 ligand signal suppressed phosphorylation of Akt, whereas it had no effect on the phosphorylation of inhibitor of receptor activator of nuclear factor- kB (I- kB) and extracellular signal-regulated kinase (ERK) 1/2, p38 and jun kinase. The CD137 ligand signal also suppressed nuclear factor of activated T cells (NFAT)-2 induction but did not affect the expression of TNF receptor-associated factor (TRAF) 6 and c-Fos. Casein kinase is also implicated in CD137 ligand signaling since its inhibition blocked CD137 ligand-mediated osteoclast differentiation and proliferation of bone marrow cells (Saito et al., 2004). A recognition site for casein kinase is present in the cytoplasmic domain of CD137 ligand (Watts et al, 1999).
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