Development - EPO-induced MAPK pathway

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EPO-induced MAPK pathway

Erythropoiesis is the main pathway of pluripotent hematopoietic stem cell development into mature end stage cells. Erythropoietin (Epo) is a major lineage-specific hematopoietic growth factor required for survival, proliferation and differentiation of committed erythroid progenitor cells [1], [2], [3].

Epo exerts its effect by binding to the Epo receptor [4], composed of two identical subunits. Upon ligand binding, the two subunits dimerize and Janus kinase JAK2 is recruited to the receptor complex resulting in the phosphorylation of several tyrosine residues on Epo receptor [5], [6], [7]. Activated JAK2 initiates Epo-induced JAK/STAT signaling [8].

Once phosphorylated Epo receptor recruits and activates a number of downstream adaptors and effectors including MAPK (mitogen-activated protein kinase) cascade and JNK (Jun N-terminal Kinases) pathway [9].

Activated Epo receptor complex recruits adapter proteins Shc and GRB2, leading to activation of the classical Shc / GRB2/ SOS/ Ras/c-Raf-1/ MEK/ ERK cascade, which is involved in cell proliferation [10].

Epo receptor, adapter protein Shc and phosphatidyl-inositol polyphosphate 5-phosphatase SHIP form a complex in hematopoietic cells, and SHIP is involved in Epo-induced signaling as an adapter protein [11], [12].

Transmembrane receptor c-Kit is the receptor for mast cell growth factor (MGF). c-Kit can interact with and phosphorylate the Epo receptor, resulting in enhanced erythroid cell differentiation and proliferation [10].

Epo receptor transduces signals by activating physically associated tyrosine kinases, mainly JAK2 and Lyn, and, thereby, inducing tyrosine phosphorylation of various substrates including the Epo receptor itself, adapter proteins CrkL and c-Cbl and tyrosine kinases Syk and Btk [13], [14], [15], [16]. CrkL associates with Shc and c-Cbl in hematopoietic cells. CrkL is constitutively associated with guanine nucleotide exchange factor C3G, that also binds Shc [17]. C3G modulates activity of the Ras family GTPases, such as RAP-1A [18], which, in turn, inhibits c-Raf-1 kinase signaling [19].

Phospholipase C (PLC-gamma 1) is an adapter protein which is rapidly tyrosine phosphorylated (e.g. by Btk kinase) upon Epo stimulation. PLC-gamma 1 interacts with GRB2 and SOS2, leading to activation of the ERK pathway [20].

Phosphorylated by Btk, Syk and Lyn, phospholipase PLC-gamma also triggers activation of several isoforms of protein kinase C, including PKC-alpha and PKC-epsilon, via diacylglycerol (DAG) production and Ca(2+) influx [21], [22], [23], [24]. PKC isoforms, in turn, can phosphorylate c-Raf-1 kinase, leading to MAPK cascade activation [25], [26].

In primary human erythroid progenitor cells, phosphatidylinositol-3 kinase, PI3K-gamma, is activated by low concentration of Epo. MEK1 and ERK1/2 kinases, through a Raf-independent signaling pathway, are signal mediators of PI3K-gamma [25]. PI3K-gamma is activated, probably, by H-Ras [27] and/or G-proteins beta/gamma [28].

Epo stimulation activates guanine nucleotide exchange factor VAV-1 [29]. VAV-1 is involved in proliferative signals in hematopoietic cells via activation of small GTPase Rac1 that stimulates both JNK1-3 kinases and MEK (MEK1 and MEK2)/ERK1/2 cascade [26], [30], [31], [32], [33], [34]. JNK1-3 and ERK1/2 kinases, in turn, phosphorylate transcription factors Elk-1, c-Jun and c-Fos that are crucial for cell proliferation [35], [36], [37].

References:

  1. Goodnough LT, Skikne B, Brugnara C
    Erythropoietin, iron, and erythropoiesis. Blood 2000 Aug 1;96(3):823-33
  2. Gabrilove J
    Overview: erythropoiesis, anemia, and the impact of erythropoietin. Seminars in hematology 2000 Oct;37(4 Suppl 6):1-3
  3. Bieber E
    Erythropoietin, the biology of erythropoiesis and epoetin alfa. An overview. The Journal of reproductive medicine 2001 May;46(5 Suppl):521-30
  4. Youssoufian H, Longmore G, Neumann D, Yoshimura A, Lodish HF
    Structure, function, and activation of the erythropoietin receptor. Blood 1993 May 1;81(9):2223-36
  5. Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, Ihle JN
    JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 1993 Jul 30;74(2):227-36
  6. Cohen J, Altaratz H, Zick Y, Klingmuller U, Neumann D
    Phosphorylation of erythropoietin receptors in the endoplasmic reticulum by pervanadate-mediated inhibition of tyrosine phosphatases. The Biochemical journal 1997 Oct 15;327 ( Pt 2):391-7
  7. Huang LJ, Constantinescu SN, Lodish HF
    The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Molecular cell 2001 Dec;8(6):1327-38
  8. Mulcahy L
    The erythropoietin receptor. Seminars in oncology 2001 Apr;28(2 Suppl 8):19-23
  9. Nishigaki K, Hanson C, Thompson D, Yugawa T, Ruscetti S
    Activation of the Jun N-terminal kinase pathway by friend spleen focus-forming virus and its role in the growth and survival of friend virus-induced erythroleukemia cells. Journal of virology 2005 Oct;79(20):12752-62
  10. Fisher JW
    Erythropoietin: physiology and pharmacology update. Experimental biology and medicine (Maywood, N.J.) 2003 Jan;228(1):1-14
  11. Joneja B, Wojchowski DM
    Mitogenic signaling and inhibition of apoptosis via the erythropoietin receptor Box-1 domain. The Journal of biological chemistry 1997 Apr 25;272(17):11176-84
  12. Lecoq-Lafon C, Verdier F, Fichelson S, Chretien S, Gisselbrecht S, Lacombe C, Mayeux P
    Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase. Blood 1999 Apr 15;93(8):2578-85
  13. Barber DL, Mason JM, Fukazawa T, Reedquist KA, Druker BJ, Band H, D'Andrea AD
    Erythropoietin and interleukin-3 activate tyrosine phosphorylation of CBL and association with CRK adaptor proteins. Blood 1997 May 1;89(9):3166-74
  14. Duprez V, Blank U, Chretien S, Gisselbrecht S, Mayeux P
    Physical and functional interaction between p72(syk) and erythropoietin receptor. The Journal of biological chemistry 1998 Dec 18;273(51):33985-90
  15. Arai A, Kanda E, Nosaka Y, Miyasaka N, Miura O
    CrkL is recruited through its SH2 domain to the erythropoietin receptor and plays a role in Lyn-mediated receptor signaling. The Journal of biological chemistry 2001 Aug 31;276(35):33282-90
  16. von Lindern M, Schmidt U, Beug H
    Control of erythropoiesis by erythropoietin and stem cell factor: a novel role for Bruton's tyrosine kinase. Cell cycle (Georgetown, Tex.) 2004 Jul;3(7):876-9
  17. Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O
    Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells. Biochemical and biophysical research communications 1997 Oct 20;239(2):412-7
  18. Hattori S, Matsuda M
    [Activation of Rap1, antagonist to ras, by Crk-C3G]. Gan to kagaku ryoho. Cancer & chemotherapy 1997 Sep;24(11):1414-21
  19. Kolch W
    Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. The Biochemical journal 2000 Oct 15;351 Pt 2:289-305
  20. Halupa A, Chohan M, Stickle NH, Beattie BK, Miller BA, Barber DL
    Erythropoietin receptor Y479 couples to ERK1/2 activation via recruitment of phospholipase Cgamma. Experimental cell research 2005 Sep 10;309(1):1-11
  21. Myklebust JH, Smeland EB, Josefsen D, Sioud M
    Protein kinase C-alpha isoform is involved in erythropoietin-induced erythroid differentiation of CD34(+) progenitor cells from human bone marrow. Blood 2000 Jan 15;95(2):510-8
  22. Chen C, Sytkowski AJ
    Erythropoietin activates two distinct signaling pathways required for the initiation and the elongation of c-myc. The Journal of biological chemistry 2001 Oct 19;276(42):38518-26
  23. Myklebust JH, Blomhoff HK, Rusten LS, Stokke T, Smeland EB
    Activation of phosphatidylinositol 3-kinase is important for erythropoietin-induced erythropoiesis from CD34(+) hematopoietic progenitor cells. Experimental hematology 2002 Sep;30(9):990-1000
  24. Fan H, Sugita K, Zhai M, Nakazawa C
    [Erythropoietin Receptor-Mediated Proliferative Signal Transduction in Leukemic Cell Line KOCL-33] Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology 2001 Jun;9(2):110-114
  25. Schmidt EK, Fichelson S, Feller SM
    PI3 kinase is important for Ras, MEK and Erk activation of Epo-stimulated human erythroid progenitors. BMC biology 2004 May 18;2:7
  26. Rafiee P, Shi Y, Su J, Pritchard KA Jr, Tweddell JS, Baker JE
    Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. Basic research in cardiology 2005 May;100(3):187-97
  27. Pacold ME, Suire S, Perisic O, Lara-Gonzalez S, Davis CT, Walker EH, Hawkins PT, Stephens L, Eccleston JF, Williams RL
    Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 2000 Dec 8;103(6):931-43
  28. Guillard C, Chretien S, Pelus AS, Porteu F, Muller O, Mayeux P, Duprez V
    Activation of the mitogen-activated protein kinases Erk1/2 by erythropoietin receptor via a G(i )protein beta gamma-subunit-initiated pathway. The Journal of biological chemistry 2003 Mar 28;278(13):11050-6
  29. Shigematsu H, Iwasaki H, Otsuka T, Ohno Y, Arima F, Niho Y
    Role of the vav proto-oncogene product (Vav) in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity. The Journal of biological chemistry 1997 May 30;272(22):14334-40
  30. Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T, Gutkind JS
    The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 1995 Jun 30;81(7):1137-46
  31. Widmann C, Gibson S, Jarpe MB, Johnson GL
    Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiological reviews 1999 Jan;79(1):143-80
  32. Heo J, Thapar R, Campbell SL
    Recognition and activation of Rho GTPases by Vav1 and Vav2 guanine nucleotide exchange factors. Biochemistry 2005 May 3;44(17):6573-85
  33. Arai A, Kanda E, Miura O
    Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway. Oncogene 2002 Apr 18;21(17):2641-51
  34. Guo F, Debidda M, Yang L, Williams DA, Zheng Y
    Genetic deletion of Rac1 GTPase reveals its critical role in actin stress fiber formation and focal adhesion complex assembly. The Journal of biological chemistry 2006 Jul 7;281(27):18652-9
  35. Muszynski KW, Ohashi T, Hanson C, Ruscetti SK
    Both the polycythemia- and anemia-inducing strains of Friend spleen focus-forming virus induce constitutive activation of the Raf-1/mitogen-activated protein kinase signal transduction pathway. Journal of virology 1998 Feb;72(2):919-25
  36. Valk P, Verbakel S, von Lindern M, Lowenberg B, Delwel R
    Enhancement of erythropoietin-stimulated cell proliferation by Anandamide correlates with increased activation of the mitogen-activated protein kinases ERK1 and ERK2. The hematology journal : the official journal of the European Haematology Association / EHA 2000;1(4):254-63
  37. Chen C, Sytkowski AJ
    Erythropoietin regulation of Raf-1 and MEK: evidence for a Ras-independent mechanism. Blood 2004 Jul 1;104(1):73-80

  1. Goodnough LT, Skikne B, Brugnara C
    Erythropoietin, iron, and erythropoiesis. Blood 2000 Aug 1;96(3):823-33
  2. Gabrilove J
    Overview: erythropoiesis, anemia, and the impact of erythropoietin. Seminars in hematology 2000 Oct;37(4 Suppl 6):1-3
  3. Bieber E
    Erythropoietin, the biology of erythropoiesis and epoetin alfa. An overview. The Journal of reproductive medicine 2001 May;46(5 Suppl):521-30
  4. Youssoufian H, Longmore G, Neumann D, Yoshimura A, Lodish HF
    Structure, function, and activation of the erythropoietin receptor. Blood 1993 May 1;81(9):2223-36
  5. Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, Ihle JN
    JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 1993 Jul 30;74(2):227-36
  6. Cohen J, Altaratz H, Zick Y, Klingmuller U, Neumann D
    Phosphorylation of erythropoietin receptors in the endoplasmic reticulum by pervanadate-mediated inhibition of tyrosine phosphatases. The Biochemical journal 1997 Oct 15;327 ( Pt 2):391-7
  7. Huang LJ, Constantinescu SN, Lodish HF
    The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Molecular cell 2001 Dec;8(6):1327-38
  8. Mulcahy L
    The erythropoietin receptor. Seminars in oncology 2001 Apr;28(2 Suppl 8):19-23
  9. Nishigaki K, Hanson C, Thompson D, Yugawa T, Ruscetti S
    Activation of the Jun N-terminal kinase pathway by friend spleen focus-forming virus and its role in the growth and survival of friend virus-induced erythroleukemia cells. Journal of virology 2005 Oct;79(20):12752-62
  10. Fisher JW
    Erythropoietin: physiology and pharmacology update. Experimental biology and medicine (Maywood, N.J.) 2003 Jan;228(1):1-14
  11. Joneja B, Wojchowski DM
    Mitogenic signaling and inhibition of apoptosis via the erythropoietin receptor Box-1 domain. The Journal of biological chemistry 1997 Apr 25;272(17):11176-84
  12. Lecoq-Lafon C, Verdier F, Fichelson S, Chretien S, Gisselbrecht S, Lacombe C, Mayeux P
    Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase. Blood 1999 Apr 15;93(8):2578-85
  13. Barber DL, Mason JM, Fukazawa T, Reedquist KA, Druker BJ, Band H, D'Andrea AD
    Erythropoietin and interleukin-3 activate tyrosine phosphorylation of CBL and association with CRK adaptor proteins. Blood 1997 May 1;89(9):3166-74
  14. Duprez V, Blank U, Chretien S, Gisselbrecht S, Mayeux P
    Physical and functional interaction between p72(syk) and erythropoietin receptor. The Journal of biological chemistry 1998 Dec 18;273(51):33985-90
  15. Arai A, Kanda E, Nosaka Y, Miyasaka N, Miura O
    CrkL is recruited through its SH2 domain to the erythropoietin receptor and plays a role in Lyn-mediated receptor signaling. The Journal of biological chemistry 2001 Aug 31;276(35):33282-90
  16. von Lindern M, Schmidt U, Beug H
    Control of erythropoiesis by erythropoietin and stem cell factor: a novel role for Bruton's tyrosine kinase. Cell cycle (Georgetown, Tex.) 2004 Jul;3(7):876-9
  17. Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O
    Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells. Biochemical and biophysical research communications 1997 Oct 20;239(2):412-7
  18. Hattori S, Matsuda M
    [Activation of Rap1, antagonist to ras, by Crk-C3G]. Gan to kagaku ryoho. Cancer & chemotherapy 1997 Sep;24(11):1414-21
  19. Kolch W
    Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. The Biochemical journal 2000 Oct 15;351 Pt 2:289-305
  20. Halupa A, Chohan M, Stickle NH, Beattie BK, Miller BA, Barber DL
    Erythropoietin receptor Y479 couples to ERK1/2 activation via recruitment of phospholipase Cgamma. Experimental cell research 2005 Sep 10;309(1):1-11
  21. Myklebust JH, Smeland EB, Josefsen D, Sioud M
    Protein kinase C-alpha isoform is involved in erythropoietin-induced erythroid differentiation of CD34(+) progenitor cells from human bone marrow. Blood 2000 Jan 15;95(2):510-8
  22. Chen C, Sytkowski AJ
    Erythropoietin activates two distinct signaling pathways required for the initiation and the elongation of c-myc. The Journal of biological chemistry 2001 Oct 19;276(42):38518-26
  23. Myklebust JH, Blomhoff HK, Rusten LS, Stokke T, Smeland EB
    Activation of phosphatidylinositol 3-kinase is important for erythropoietin-induced erythropoiesis from CD34(+) hematopoietic progenitor cells. Experimental hematology 2002 Sep;30(9):990-1000
  24. Fan H, Sugita K, Zhai M, Nakazawa C
    [Erythropoietin Receptor-Mediated Proliferative Signal Transduction in Leukemic Cell Line KOCL-33] Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology 2001 Jun;9(2):110-114
  25. Schmidt EK, Fichelson S, Feller SM
    PI3 kinase is important for Ras, MEK and Erk activation of Epo-stimulated human erythroid progenitors. BMC biology 2004 May 18;2:7
  26. Rafiee P, Shi Y, Su J, Pritchard KA Jr, Tweddell JS, Baker JE
    Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways. Basic research in cardiology 2005 May;100(3):187-97
  27. Pacold ME, Suire S, Perisic O, Lara-Gonzalez S, Davis CT, Walker EH, Hawkins PT, Stephens L, Eccleston JF, Williams RL
    Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 2000 Dec 8;103(6):931-43
  28. Guillard C, Chretien S, Pelus AS, Porteu F, Muller O, Mayeux P, Duprez V
    Activation of the mitogen-activated protein kinases Erk1/2 by erythropoietin receptor via a G(i )protein beta gamma-subunit-initiated pathway. The Journal of biological chemistry 2003 Mar 28;278(13):11050-6
  29. Shigematsu H, Iwasaki H, Otsuka T, Ohno Y, Arima F, Niho Y
    Role of the vav proto-oncogene product (Vav) in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity. The Journal of biological chemistry 1997 May 30;272(22):14334-40
  30. Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, Miki T, Gutkind JS
    The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 1995 Jun 30;81(7):1137-46
  31. Widmann C, Gibson S, Jarpe MB, Johnson GL
    Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiological reviews 1999 Jan;79(1):143-80
  32. Heo J, Thapar R, Campbell SL
    Recognition and activation of Rho GTPases by Vav1 and Vav2 guanine nucleotide exchange factors. Biochemistry 2005 May 3;44(17):6573-85
  33. Arai A, Kanda E, Miura O
    Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway. Oncogene 2002 Apr 18;21(17):2641-51
  34. Guo F, Debidda M, Yang L, Williams DA, Zheng Y
    Genetic deletion of Rac1 GTPase reveals its critical role in actin stress fiber formation and focal adhesion complex assembly. The Journal of biological chemistry 2006 Jul 7;281(27):18652-9
  35. Muszynski KW, Ohashi T, Hanson C, Ruscetti SK
    Both the polycythemia- and anemia-inducing strains of Friend spleen focus-forming virus induce constitutive activation of the Raf-1/mitogen-activated protein kinase signal transduction pathway. Journal of virology 1998 Feb;72(2):919-25
  36. Valk P, Verbakel S, von Lindern M, Lowenberg B, Delwel R
    Enhancement of erythropoietin-stimulated cell proliferation by Anandamide correlates with increased activation of the mitogen-activated protein kinases ERK1 and ERK2. The hematology journal : the official journal of the European Haematology Association / EHA 2000;1(4):254-63
  37. Chen C, Sytkowski AJ
    Erythropoietin regulation of Raf-1 and MEK: evidence for a Ras-independent mechanism. Blood 2004 Jul 1;104(1):73-80

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