ptin melanocortin axis exerts a central role in the control of body weight. Leptin signaling occurs primarily via Jak-Stat signaling pathway emplying the Jak2-Stat3 combination. Leptin binding to its receptor, a single membrane spanning protein with structural similarity to the class I cytokine receptor family, leads to receptor oligomerization, binding to and activation of Jak2. Jak2 activation involves autophosphorylation and phosphorylation of tyrosine residues on the cytoplasmic domain of leptin receptor. P-Y1138 can then recruit Stat3 to the Lepr-Jak2 complex followed by Stat3 phosphorylation. P-Stat3 dimerizes and translocates to the nucleus where it regulates the transcription of target genes, including Socs3. Socs3 binding to P-Y985 on leptin receptor and other sites within the Lepr-Jak2 complex provides a negative regulatory feedback loop. Inhibitory effects are also imparted by Ptpn1. In vitro, Ptpn1 dephophorylates both Jak2 and Stat3. Other pathways activated by leptin include phosphatidylinositol 3-kinase-Akt signaling via Jak2 activation of Irs (insulin receptor substrates) and the Raf/Mek/Erk module of MAPK cascades via Ptpn11 acting upstream of the two pathways, respectively. It has been shown that Sh2bpsm1 - a protein containing both PH and SH2 (plekstrin and src homology 2 domains) -  can recruit Irs1 and Irs2 in response to leptin, form a ternary complex with Irs1 or Irs2 and activate Jak2 to promote tyrosine phopshorylation of Irs proteins by Jak2. It is worth mentioning that Stat and Socs proteins as well as Ptpn11 contain SH2 - src homology 2 - domains that bind to phosphotyrosines containing targets. Ptpn11, acting upstream of ERK1/2 pathway can interact with either phosphorylated leptin receptor or Jak2.To see the ontology report for annotations, GViewer and download, click here

[click to see the ontology report for related GO term GO:0033210]...(less)