Fig. 7
From: Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy
Jak/STAT pathway. The corresponding cytokine or growth factor ligand binds to the cell surface receptor prompting activated JAK2 protein to phosphorylate tyrosine residues in the cytoplasmic domain of the receptor. More so, JAK2 also phosphorylates recruited signal transducer and activator of transcription (STAT) which results in STAT dimerization via conserved Src homology 2 (SH2) domains. STAT dimers then translocate to the nucleus where they induce transcription of target genes. In addition, JAK acts as a docking site for SH2 containing adapter proteins including Src homology 2 domain-containing phosphatase 2 (SHP2), growth factor receptor bound protein-2 (GRB2), and Src homology 2 domain-containing transforming protein (SHC). GRB2 which is associated with Son of Sevenless (SOS) can bind the tyrosine phosphorylated receptor directly or indirectly by way of the Src homology 2 domain-containing protein (SHC). This binding results in the translocation of SOS to the membrane. At the membrane, SOS exchanges GDP for GTP on Ras guanine nucleotide-binding proteins. Ras-GTP can then activate MAPK cascade. Aside from RAS, JAK/STAT also interacts with PI3 and AKT pathways [65]. Under normal conditions gene expression is regulated by negative feedback mechanisms including the production of the negative regulator suppressors of cytokine signaling (SOCS)