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Review
. 2001 Dec;108(12):1735-40.
doi: 10.1172/JCI14662.

The central role of SOCS-3 in integrating the neuro-immunoendocrine interface

C J Auernhammer  1 , S Melmed
Affiliations
Review

The central role of SOCS-3 in integrating the neuro-immunoendocrine interface

C J Auernhammer et al. J Clin Invest. 2001 Dec.
No abstract available

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Figures

Figure 1
Figure 1
Corticotroph SOCS-3 as an intracellular suppressor of cytokine signaling. Corticotroph SOCS-3 inhibits STAT-dependent POMC gene expression by negatively interfering with LIF-induced activation of the JAK-STAT cascade. In contrast, CRH-induced POMC gene expression is not affected by SOCS-3. LIF stimulation of the corticotroph results in rapid upregulation of SOCS-3 by a STAT-dependent mechanism. Thus, LIF-induced activation of corticotroph POMC gene activation is limited by parallel induction of SOCS-3 expression, rendering the cell resistant to further JAK-STAT activation. On the other hand, autoregulation of STAT-dependent SOCS-3 gene expression and rapid degradation of SOCS-3 protein by the proteasome pathway enable the cell to restore its functional status. LIF and CRH synergistically induce POMC promoter activity. LIF activates POMC promoter activity not only by direct binding of activated STATs, but also indirectly by inducing STAT-dependent expression of transcription factors c-fos and JunB. CRH also induces SOCS3 promoter activity by binding of c-fos and JunB. Thus, CRH indirectly inhibits LIF-induced POMC promoter activation and downregulates the synergistic cross-talk of CRH and LIF on POMC promoter activity. Adapted from ref. and ref. with permission.
Figure 2
Figure 2
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. with permission.
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References

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