The JAK/STAT signaling pathway transmits a signal from outside the cell eventually resulting in DNA transcription and activity in the cell. Leptin (a product of the obese gene) can induce a cascade of events through its receptor (LRb; also known as Ob-Rb or the long isoform) and the JAK/STAT pathway. Siginificantly, Leptin mediated signaling through the JAK2/STAT3 pathway affects appetite and has been implicated in various carcinomas. Constitutively associated with the LRb is the Janus kinase 2 (JAK2) whose association and subsequent activation requires the so called Box 1 proline-rich motif found on all LRb receptors. Upon leptin binding, the receptor homodimerizes bringing two JAK2 in proximity to allow trans-phosphorylation of the JAK2's which activates them and leads to their phosphorylation of the receptor which creates binding opportunities for proteins that possess phosphotyrosine-binding SH2 domains. The signal transducer and activator of transcription (STAT) proteins possess such SH2 domains. Hence STAT3 recruitment via its SH2 domains results in STAT3 phosphorylation followed by its dimerization and translocation to the nucleus. Within the nucleus, STAT3 can bind promoters and affect expression of DNA sequences which control basic cell functions such as cell growth, differentiation and death. In addition, the activated JAK2 phosphorylates and activates numerous other STATs and proteins, such as IRS-1, PI3K and AkT. This LRb/JAK2/STAT3 signaling pathway is widely expressed in the brain and can control appetite by affecting the production of the anorexigenic peptide α-MSH.
Obesity also greatly influences the risk of many common forms of cancer with hepatocellular carcinoma exhibiting the highest relative-risk (4.52X) increase for obese men compared with all the cancers studied. Studies have shown that treatment with leptin increased the proliferation of HepG2 and Huh7 cells and involved the activation of STAT3, PI3K, Akt and Erk via JAK2. Temporally, studies demonstrated that JAK2/STAT3 activation followed leptin treatment and was upstream of PI3K, Akt and ERK phosphorylation. In addition, leptin was found to increase the migration capability of hepatocellular carcinoma cells and correlated with JAK2/STAT3 activation demonstrated by using the JAK/STAT inhibitor AG490.
JAK-Stat Signaling Subcategories