Ettenberg, A. signaling. Interleukin 6 (IL-6) is a typical cytokine and mediates a variety of biological activities, including cell proliferation or differentiation, acute-phase reaction, and inflammation Elf2 (3, 5, 35, 38, 55), in a wide range of tissues. The IL-6 receptor system is composed of two ligand-binding alpha receptor subunits, IL-6R, and two gp130 subunits; gp130 is a type BETP I transmembrane glycoprotein and functions in the receptor complexes of other IL-6 family cytokines, including IL-11, LIF, OSM, CNTF, and CT1 (20, 21, 37, 57, 73). While it is soluble, the extracellular portion of IL-6R (soluble IL-6R [sIL-6R]) binds IL-6, and gp130 transduces the signal (25). The binding of IL-6 to its receptor induces homodimerization of gp130, which results in the transphosphorylation and activation of associated Janus tyrosine kinases (Jaks) and the phosphorylation of gp130 at multiple tyrosine residues (50, 67). Tyrosine phosphorylation creates special docking sites for signaling molecules containing SH2 and/or TKB (tyrosine kinase-binding) domains. gp130-mediated signals activate two major signaling cascades, the STAT3 and the MAP kinase pathways (22, 42). Among the six tyrosine residues within the cytoplasmic region of gp130, the five phospohotyrosines most proximal to the C terminus bind STAT3. STAT3 forms a homodimer upon phosphorylation and eventually translocates to the nucleus (9, 66). Thus, proliferation- and/or differentiation-promoting signals from gp130 are mediated by the four most C-terminal tyrosine residues. In contrast, the other tyrosine residue, tyrosine 759 (Y759, corresponding to Y757), which is the second-closest tyrosine to the membrane, mediates proliferation- and/or differentiation-inhibiting signals (53, 54) through the binding of a tyrosine phosphatase, SHP2. The SHP2 signal eventually activates the MAP kinases, ERK1/2, and SOCS3, which is transcriptionally induced by IL-6, LIF, and other factors that activate STAT3 and has been shown to regulate the strength of cytokine signals by inhibiting the Jaks (63, 68). Despite these BETP findings, the details of how Y759 mediates the inhibitory signal through SHP2 activity have remained unclear. The duration and strength of receptor-mediated signals are tightly regulated. This is accomplished by terminal signal inactivation via the endocytosis and degradation of activated receptors and of their associated signaling proteins. Following ligand binding, growth factor receptors, such as the epidermal growth factor receptor (EGFR), are rapidly internalized from the cell surface via several mechanisms, including clathrin-dependent endocytosis (31, 40). Internalized receptors are initially delivered to early endosomes, which mature into late endosomes and multivesicular bodies (MVBs). EGFRs are sorted into intraluminal vesicles within the MVBs as MVB cargoes. An alteration in their topology allows the cargoes to be eventually destroyed by the lysosomes (19, 23). These processes are essential to avoid constitutive signaling that would lead to tumorigenesis. For many receptors, ubiquitination plays a key role in endosomal trafficking (33, 49). Ubiquitin (Ub) is an evolutionarily conserved protein consisting of 76 amino acids that can be covalently attached to a target protein via a process known as ubiquitination (32, 61). Attachment of a single Ub to a target lysine residue is called monoubiquitination; the formation of Ub chains is called polyubiquitination. The type of Ub modification largely determines the fate of the ubiquitinated proteins. Monoubiquitination is associated with the endocytosis and lysosomal sorting of plasma membrane proteins (27), but the formation of lysine BETP 48 (K48)-linked polyubiquitin chains is the primary signal that targets the protein to the 26S proteasome for degradation (49, 71). K63-linked polyubiquitin chains also serve nonproteolytic functions, including acting as a signal for endocytosis, DNA repair, and kinase activation, although BETP these processes may themselves be involved in proteolytic functions. Regardless of these complexities, it is clear that these two forms of ubiquitination regulate different cellular processes that may be indirectly involved with proteolytic degradation (34). Specificity in the ubiquitination process is mediated by E3 ligases (15). The Cbl family of Ub ligases plays pivotal roles in the polyubiquitination of EGFR (36). c-Cbl binds directly to phosphorylated EGFRs via its TKB domain, while the RING finger domain of Cbl recruits Ub-conjugating enzymes (E2, Ubc) and mediates the transfer of Ub to the receptor (26, 62). However, the role(s) of ubiquitination and E3s in receptor trafficking and.