Inhibitory effects of SOCS-3 and SHP-1 on LIF-mediated gene expression. (a) The tyrosine kinase JAK2 and tyrosine phosphatase SHP-1 are constitutively expressed but remain inactive in the unstimulated corticotroph. In contrast, SOCS-3 expression in the unstimulated corticotroph is minimal. (b) LIF binding rapidly induces the LIF receptor (LIFR) and gp130 subunits to form a heterodimer receptor complex. Receptor complex formation leads to autophosphorylation of receptor-associated JAK2, followed by tyrosine phosphorylation of the receptor’s cytoplasmic domain and recruitment of STAT proteins to the receptor complex. Subsequent tyrosine phosphorylation of STATs enables homo- or heterodimerization of STAT proteins. The dimerized STAT complexes translocate to the nucleus and bind to specific STAT-binding elements in the promoter region of various genes, among them SOCS3. (c) The tyrosine phosphatase SHP-1 is activated by LIF, showing maximum catalytic activity at 30 minutes. JAK2 and its substrates are dephosphorylated by SHP-1. Thus, SHP-1 is a constitutively expressed and rapidly activated inhibitor of JAK-STAT signaling in the corticotroph. (d) STAT-dependent SOCS3 gene expression is induced severalfold by LIF within 30 minutes. SOCS-3 protein associated with JAK2 is detectable 40–60 minutes after LIF stimulation. Association of SOCS-3 with JAK2 inhibits JAK2 activity. Thus, SOCS-3 inhibits JAK-STAT signaling in the corticotroph, its expression rapidly up- and downregulated by LIF and negative autoregulation of its own STAT-dependent gene expression. SOCS-3 is rapidly degraded by a proteasome-dependent pathway, allowing the corticotroph to return to its basal state, in which it can once again be activated by LIF or other gp130 cytokines (see a). Reproduced from ref. 18 with permission.