Skip to main content

Advertisement

Fig. 1 | Multiple Sclerosis and Demyelinating Disorders

Fig. 1

From: The role of puberty and adolescence in the pathobiology of pediatric multiple sclerosis

Fig. 1

Mechanisms of Leptin signalling in immune and neuroendocrine cells. Leptin binds to one of its receptors, LEPRb, activating JAK2 by auto-phosphorylation or cross-phosphorylation, and phosphorylates tyrosine residues in the receptor’s cytoplasmic domain. Four of the phosphorylated residues [974, 985, 1077, 1138] function as docking sites for cytoplasmic adaptors for STAT factors, particularly STAT3, which dimerizes translocating into the nucleus, where it induces expression of SOCS3, FOS and JUN genes. SOCS3 participates in a feedback loop that inhibits Leptin signalling by binding to phosphorylated tyrosines. SHP-2 is recruited to Tyr985 and Tyr974 and activates ERK1/2 and p38 MAPK pathways through the adaptor protein GRB2, ultimately inducing FOS and JUN gene expression [FOS and JUN encode for fos and jun proto-oncogene proteins, which form heterodimers (C-fos:c-jun) resulting in the formation of AP-1 (Activator Protein-1) complex, which binds DNA at AP-1 specific sites at the promoter and enhancer regions of target genes and converts extracellular signals into changes of gene expression]. PTP-1B is localized on the surface of the endoplasmic reticulum, and is involved in negative regulation of LEPRb signalling through dephosphorylation of JAK2 after internalization of the LEPRb complex; the endoplasmic reticulum is also the site of action (via Ca++) of the IP3-PIP2-mediated pathway of the Kissprotein1, which in turn modulates GnRH secretion and ultimately LH and FSH secretion [neuroendocrine cells are hereby represented as if they were inside the membrane for practical purposes: in the real pathways the Kiss1 protein binds to the Kiss1 receptor (R), which is expressed on the membrane surface of both immune and neuroendocrine cells: the latter cells promote secretion of GnRH, which in turn stimulate secretion of LH and FSH]. JAK2 can also induce phosphorylation of the IRS1 and 2 proteins, which are responsible for PI3K/AKT and mTOR pathway activation

Back to article page