The JAK-STAT signal-transduction pathway The JAK-STAT signal-transduction pathway. (A) Cytokine ligands normally bind cytokine receptors, resulting in JAK2 phosphorylation, activation of Stat signaling proteins, and phosphorylation and activation of downstream signaling pathways. These include Stat-mediated transcription, mitogen-activated protein kinase (MAPK) signaling, and the phosphotidylinositol 3-kinase (PI3K)–Akt pathway. (B) The JAK2V617F and JAK2 exon 12 mutant kinases bind cytokine receptors and are phosphorylated in the absence of ligand. Constitutive activation of JAK2 leads to ligand-independent activation of downstream signaling pathways. (C) MPL-mutant thrombopoietin receptors are able to phosphorylate wild-type JAK2 in the absence of thrombopoietin and thereby trigger the activation of downstream signaling pathways. Negative regulation of JAK2 signaling is normally mediated by suppressor of cytokine signaling (Socs) proteins, most notably SOCS1 and SOCS3; recent data indicate that the JAK2V617F allele might escape inhibition by SOCS3. (Adapted from Levine RL et al: Nat Rev Cancer 7(9):673-83, 2007, with permission.) Source: The Classic Myeloproliferative Neoplasms: Chronic Myelogenous Leukemia, Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis, The Online Metabolic and Molecular Bases of Inherited Disease Citation: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. The Online Metabolic and Molecular Bases of Inherited Disease; 2014 Available at: https://ommbid.mhmedical.com/DownloadImage.aspx?image=/data/books/971/ch59_2fg1.png&sec=62669590&BookID=971&ChapterSecID=62669557&imagename= Accessed: January 02, 2018 Copyright © 2018 McGraw-Hill Education. All rights reserved