Figure 3.

Leptin receptor signaling. LRb is constitutively associated with Janus family of tyrosine kinase 2 (JAK2). Leptin binding to LRb triggers autophosporylation of JAK2^155–157 and subsequent phosphorylation of cytoplasmic LRb tyrosine residues, including Y1138 and Y985. Phosphorylation of Y1138 recruits STAT3, which is then phosphorylated and translocated into the nucleus to alter gene expression, including upregulation of suppressor of cytokine signaling 3 (SOCS3) expression.^142,155 SOCS3 binds to Y985 as a negative feedback regulator of LRb signaling.¹⁴¹ Y985 serves dual roles in that its phosphorylation promotes binding of the tyrosine phosphatase SHP-2, leading to downstream Erk1/2 phosphorylation/activation.^155,158 In cultured cells, LR activation also triggers phosphoinositide 3-kinase (PI3K)-Akt signaling,^86,89,93,94 although it is unclear whether Akt phosphorylation occurs in vivo.^98,159–161 Both Erk1/2 (via p90RSK) and Akt phosphorylation can lead to downstream GSK3 phsophorylation/inhibition.⁸⁶ Signaling molecules that are known to affect APP processing are highlighted in blue italics.