Fig. 3

Schematic representation of leptin-mediated signaling. Leptin binds to Ob-Rb and activates Janus-family tyrosine kinase 2 (JAK2) by autophosphorylation. Activated JAK2 then phosphorylates the other tyrosine residues Tyr985, Tyr1077, and Tyr1138. These phosphorylated amino acid residues act as sites for the binding of intracellular signaling molecules. Tyr1138 on Ob-Rb is crucial for STAT3 activation, which stimulates SOCS3 expression as well as other genes expression are involved in cell proliferation. SOCS3 can negatively regulate leptin signaling via inhibiting JAK2 activity in a feedback mechanism. JAK2 phosphorylation can lead to activation of PI3-Kinase /AKT pathway trough JAK2 as well as via insulin substrate. The activated PI3-kinase/AKT regulates cell proliferation via modulation of antiapoptotic genes such as BcxL and XIAP. 17β-estradiol, an estrogen steroid, can reverse leptin-induced migration via PI3K-Akt pathway. Ob-Rb can also activate MAP-kinase and COX-2 signaling pathways. Leptin-mediated increase of COX-2 expression is correlated with increased proliferation. Leptin induces EMT via PI3K/Akt/mTOR pathway, associated with malignant transformation and peritoneal dissemination. Leptin binding also upregulates uPA, mediated by RhoA/ROCK pathway, inducing cancer cell migration and invasiveness. PI3K/AKT and JAK/STAT pathways can also upregulate uPA expression. Leptin-induced migration/invasion via the mentioned pathways maintains stem-like properties and mesenchymal phenotype, potentially explaining the poor survival outcome in obese women