Figure 2. Role of phosphotyrosines of OB-Rb in leptin signalling.

JAK2 associates with the receptor via the box1 motif. The long isoform leptin (L) receptor (OB-Rb) contains four important tyrosine residues (Tyr⁹⁷⁴, Tyr⁹⁸⁵, Tyr¹⁰⁷⁷ and Tyr¹¹³⁸). These phosphorylated tyrosine residues provide docking sites for signalling proteins with SH2 domains. Most importantly, Tyr¹¹³⁸ recruits the transcription factor STAT3, which is subsequently phosphorylated by JAK2, dimerizes and translocates to the nucleus, where it induces SOCS3 and POMC (pro-opiomelanocortin) expression, while repressing AgRP (agouti-related peptide). SOCS proteins inhibit signalling by binding to phosphorylated JAK proteins or interacting directly with tyrosine-phosphorylated receptors. The ability of SOCS3 to inhibit leptin-stimulated phosphorylation of JAK2 and ERK provides a negative-feedback mechanism on the leptin signalling system. Grb-2, growth factor receptor binding-2.