American Society of Hematology

Fig. 4.

$Fig. 4. The classical Ras-to-MAPK cascade. / (A) Signaling by cytokine receptors. The IL-3, IL-5, and GM-CSF receptors consist of a ligand-specific α-subunit and a common β-subunit. The β-subunit binds the NRTKs Lyn, Fes, and JAK2. After ligand binding, the α- and β-subunits are thought to dimerize, thus activating the receptor-bound NRTKs and subsequently causing a cascade of tyrosine phosphorylations. The phosphotyrosine residues represent docking sites for various signaling molecules (eg, Shc, SHP-2). ERKs are activated via the classical Ras-to-MAPK pathway. In addition, the MAPKs p38 and JNK become activated. The activation pathway is not completely understood, but some lines of evidence support the involvement of Ras or HPK-1 (hematopoietic progenitor kinase, a mammalian Ste20-related protein). Activated JAK2 phosphorylates the STAT (signal transducers and activators of transcription) family of nuclear factors which form heterodimers and homodimers, thus causing their translocation to the nucleus and subsequent binding to γ-activating sequences of the promoter region of various genes.4142 (B) Signaling by receptor tyrosine kinases. Extracellular stimuli such as mitogens or stress result in the intracellular activation of different MAPK cascades. The ERK-1/2 pathway is activated by mitogens in all cells and is an essential part of mitogenic signaling. Translocation of a fraction of activated ERKs to the nucleus subsequently leads to activation of transcription factors such as Elk-1, CREB, SRF, and Fos.40 The Raf kinases connect upstream tyrosine kinases and Ras with downstream serine/threonine kinases. When Ras becomes GTP-loaded, Rafs bind to Ras. It is unclear if Ras-Raf binding is itself always sufficient to activate the Raf kinases, which subsequently phosphorylate and activate the downstream MEKs. GTP-Ras also binds and activates PI-3K and Ral-GEF. PI-3K produces lipid second messengers, which activate AKT (Akt kinase) and ncPKC. Ral-GEF activates Ral-GTPases by promoting the GTP-bound state of Ral. Ral-GTP binds to Ral-BP1 (a GAP for CDC42 and Rac), phospholipase D (PLD1), and Ca2+ calmodulin (CaCM). (I) Inhibitors of Ras membrane association (eg, FTI, GGTI, PPMTI, and REPI); (II) sulindac; (III) MEK inhibitors (eg, PD098059, U0126, and Ro 09-2110). The thick, black arrows show the classical Ras-to-MAPK cascade. The thick, open arrows represent the Ras-to-Ral and the Ras–to–PI-3K signaling pathways. The STAT pathway is shown on the left.$

The classical Ras-to-MAPK cascade.

(A) Signaling by cytokine receptors. The IL-3, IL-5, and GM-CSF receptors consist of a ligand-specific α-subunit and a common β-subunit. The β-subunit binds the NRTKs Lyn, Fes, and JAK2. After ligand binding, the α- and β-subunits are thought to dimerize, thus activating the receptor-bound NRTKs and subsequently causing a cascade of tyrosine phosphorylations. The phosphotyrosine residues represent docking sites for various signaling molecules (eg, Shc, SHP-2). ERKs are activated via the classical Ras-to-MAPK pathway. In addition, the MAPKs p38 and JNK become activated. The activation pathway is not completely understood, but some lines of evidence support the involvement of Ras or HPK-1 (hematopoietic progenitor kinase, a mammalian Ste20-related protein). Activated JAK2 phosphorylates the STAT (signal transducers and activators of transcription) family of nuclear factors which form heterodimers and homodimers, thus causing their translocation to the nucleus and subsequent binding to γ-activating sequences of the promoter region of various genes.41,42 (B) Signaling by receptor tyrosine kinases. Extracellular stimuli such as mitogens or stress result in the intracellular activation of different MAPK cascades. The ERK-1/2 pathway is activated by mitogens in all cells and is an essential part of mitogenic signaling. Translocation of a fraction of activated ERKs to the nucleus subsequently leads to activation of transcription factors such as Elk-1, CREB, SRF, and Fos.40 The Raf kinases connect upstream tyrosine kinases and Ras with downstream serine/threonine kinases. When Ras becomes GTP-loaded, Rafs bind to Ras. It is unclear if Ras-Raf binding is itself always sufficient to activate the Raf kinases, which subsequently phosphorylate and activate the downstream MEKs. GTP-Ras also binds and activates PI-3K and Ral-GEF. PI-3K produces lipid second messengers, which activate AKT (Akt kinase) and ncPKC. Ral-GEF activates Ral-GTPases by promoting the GTP-bound state of Ral. Ral-GTP binds to Ral-BP1 (a GAP for CDC42 and Rac), phospholipase D (PLD1), and Ca²⁺ calmodulin (CaCM). (I) Inhibitors of Ras membrane association (eg, FTI, GGTI, PPMTI, and REPI); (II) sulindac; (III) MEK inhibitors (eg, PD098059, U0126, and Ro 09-2110). The thick, black arrows show the classical Ras-to-MAPK cascade. The thick, open arrows represent the Ras-to-Ral and the Ras–to–PI-3K signaling pathways. The STAT pathway is shown on the left.

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