Development - EPO-induced Jak-STAT pathway

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EPO-induced Jak-STAT pathway

Erythropoiesis is a major pathway by which a pluripotent hematopoietic stem cell gives rise to mature end stage cells. Erythropoietin (EPO) is a 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], which is 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 the receptor. These phosphorylated tyrosine residues form docking sites for several molecules, including the signal transducer and activator of transcription (STAT) transcription factors. The STAT molecules are phosphorylated on a single tyrosine residue by JAK kinases, leading to dimerization and subsequent translocation to the nucleus where they act as transcription factors [5]. STAT5 factors (STAT5A and STAT5B) are the most prominent STAT proteins activated by EPO receptor [6], [7]. STAT3 and STAT1 are also, albeit to a lesser extent, activated by EPO stimulation [8], [9], [10].

CrkL, an adapter protein that is activated by binding to the EPO receptor, can directly associate with STAT5A and inhibit its DNA binding activity [11], [12]. Kinases c-Src and JAK2 cooperatively tyrosine-phosphorylate STAT5 [13].

EPO-induced activation of STATs is mainly involved in cell survival via up-regulation of the expression of antiapopototic factors, such as Bcl-XL, XIAP, Pim-1, Bcl-2 and transcription factor c-Myc [10], [14], [15], [16], [17].

Protein kinase Lyn directly associates with EPO receptor, binds to JAK2, and phosphorylates EPO receptor and STAT5 at tyrosine residues, thus playing a role in activation of JAK2/STAT5 signaling [18].

Calcium-binding protein Calmodulin physically interacts with EPO receptor and enhances JAK2-mediated signaling [19].

EPO also activates the canonical kinase cascade H-Ras - c-Raf-1- MEK1/2 - ERK1/2 by recruiting Shc/GRB2/Sos complex to the EPO receptor [20], [21].

Besides tyrosine phosphorylation of STAT3 by JAK2, leading to nuclear translocation, STAT3 proteins can be serine-phosphorylated by MSK1 kinase, which is activated upon MEK1/2 - ERK1/2 signal transduction cascade. It was demonstrated that serine phosphorylation of STAT3 augments its transactivational potential in erythroid cells [22].

c-Fes tyrosine kinase is also involved in EPO-induced activation of STAT3 [9], [23].

Expression of suppressors of cytokine signaling proteins SOCS1 and SOCS3 (, or CISH (Cytokine-inducible SH2-containing protein) negatively regulates EPO-mediated Jak-STAT signaling [24], [25]. On the other hand, SOCS3 binds to the GTPase activating protein p120GAP that attenuates H-Ras inhibition and activates MEK1/2 - ERK1/2 cascade to ensure cell survival and proliferation [26].

The adaptor protein APS is tyrosine phosphorylated by JAK2, followed by recruitment of the adaptor protein c-Cbl into the EPO receptor/JAK2 complex, which inhibits the JAK-STAT pathway [27].

Protein tyrosine phosphatases SHP-1 and SHP-2 are recruited to the EPO receptor/JAK2 complex and dephosphorylate JAK2, inhibiting JAK-STAT signaling [28], [29], [30]. SHP-1 is critical in negative regulation of STAT5 activation. SHP-1 is recruited to EPO receptor/JAK2 complex that results in the recruitment of Grb2 and its associated protein SOCS1. SOCS1 is targeted to JAK2, leading to JAK2/STAT5 signaling inactivation [31].

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. Mulcahy L
    The erythropoietin receptor. Seminars in oncology 2001 Apr;28(2 Suppl 8):19-23
  6. Smithgall TE, Briggs SD, Schreiner S, Lerner EC, Cheng H, Wilson MB
    Control of myeloid differentiation and survival by Stats. Oncogene 2000 May 15;19(21):2612-8
  7. Richmond TD, Chohan M, Barber DL
    Turning cells red: signal transduction mediated by erythropoietin. Trends in cell biology 2005 Mar;15(3):146-55
  8. Kirito K, Uchida M, Yamada M, Miura Y, Komatsu N
    A distinct function of STAT proteins in erythropoietin signal transduction. The Journal of biological chemistry 1997 Jun 27;272(26):16507-13
  9. Kirito K, Nakajima K, Watanabe T, Uchida M, Tanaka M, Ozawa K, Komatsu N
    Identification of the human erythropoietin receptor region required for Stat1 and Stat3 activation. Blood 2002 Jan 1;99(1):102-10
  10. Kirito K, Nagashima T, Ozawa K, Komatsu N
    Constitutive activation of Stat1 and Stat3 in primary erythroleukemia cells. International journal of hematology 2002 Jan;75(1):51-4
  11. Ota J, Kimura F, Sato K, Wakimoto N, Nakamura Y, Nagata N, Suzu S, Yamada M, Shimamura S, Motoyoshi K
    Association of CrkL with STAT5 in hematopoietic cells stimulated by granulocyte-macrophage colony-stimulating factor or erythropoietin. Biochemical and biophysical research communications 1998 Nov 27;252(3):779-86
  12. 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
  13. Okutani Y, Kitanaka A, Tanaka T, Kamano H, Ohnishi H, Kubota Y, Ishida T, Takahara J
    Src directly tyrosine-phosphorylates STAT5 on its activation site and is involved in erythropoietin-induced signaling pathway. Oncogene 2001 Oct 4;20(45):6643-50
  14. Lacombe C, Mayeux P
    The molecular biology of erythropoietin. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 1999;14 Suppl 2:22-8
  15. Wei L, Han BH, Li Y, Keogh CL, Holtzman DM, Yu SP
    Cell death mechanism and protective effect of erythropoietin after focal ischemia in the whisker-barrel cortex of neonatal rats. The Journal of pharmacology and experimental therapeutics 2006 Apr;317(1):109-16
  16. Menon MP, Karur V, Bogacheva O, Bogachev O, Cuetara B, Wojchowski DM
    Signals for stress erythropoiesis are integrated via an erythropoietin receptor-phosphotyrosine-343-Stat5 axis. The Journal of clinical investigation 2006 Mar;116(3):683-94
  17. Zhang F, Wang S, Cao G, Gao Y, Chen J
    Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia. Neurobiology of disease 2007 Jan;25(1):45-53
  18. Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O
    Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood 1998 May 15;91(10):3734-45
  19. Kakihana K, Yamamoto M, Iiyama M, Miura O
    Calmodulin physically interacts with the erythropoietin receptor and enhances Jak2-mediated signaling. Biochemical and biophysical research communications 2005 Sep 23;335(2):424-31
  20. Tian X, Feig LA
    Basis for signaling specificity difference between Sos and Ras-GRF guanine nucleotide exchange factors. The Journal of biological chemistry 2001 Dec 14;276(50):47248-56
  21. Zhang J, Lodish HF
    Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors. Blood 2004 Sep 15;104(6):1679-87
  22. Wierenga AT, Vogelzang I, Eggen BJ, Vellenga E
    Erythropoietin-induced serine 727 phosphorylation of STAT3 in erythroid cells is mediated by a MEK-, ERK-, and MSK1-dependent pathway. Experimental hematology 2003 May;31(5):398-405
  23. Sangrar W, Gao Y, Bates B, Zirngibl R, Greer PA
    Activated Fps/Fes tyrosine kinase regulates erythroid differentiation and survival. Experimental hematology 2004 Oct;32(10):935-45
  24. Hortner M, Nielsch U, Mayr LM, Heinrich PC, Haan S
    A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor. European journal of biochemistry / FEBS 2002 May;269(10):2516-26
  25. Jegalian AG, Wu H
    Differential roles of SOCS family members in EpoR signal transduction. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2002 Aug;22(8):853-60
  26. Cacalano NA, Sanden D, Johnston JA
    Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras. Nature cell biology 2001 May;3(5):460-5
  27. Wakioka T, Sasaki A, Mitsui K, Yokouchi M, Inoue A, Komiya S, Yoshimura A
    APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 1999 May;13(5):760-7
  28. Carter-Su C, Rui L, Stofega MR
    SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone. Recent progress in hormone research 2000;55:293-311
  29. Cheung JY, Miller BA
    Molecular mechanisms of erythropoietin signaling. Nephron 2001 Mar;87(3):215-22
  30. De Souza D, Fabri LJ, Nash A, Hilton DJ, Nicola NA, Baca M
    SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities. Biochemistry 2002 Jul 23;41(29):9229-36
  31. Minoo P, Zadeh MM, Rottapel R, Lebrun JJ, Ali S
    A novel SHP-1/Grb2-dependent mechanism of negative regulation of cytokine-receptor signaling: contribution of SHP-1 C-terminal tyrosines in cytokine signaling. Blood 2004 Feb 15;103(4):1398-407

  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. Mulcahy L
    The erythropoietin receptor. Seminars in oncology 2001 Apr;28(2 Suppl 8):19-23
  6. Smithgall TE, Briggs SD, Schreiner S, Lerner EC, Cheng H, Wilson MB
    Control of myeloid differentiation and survival by Stats. Oncogene 2000 May 15;19(21):2612-8
  7. Richmond TD, Chohan M, Barber DL
    Turning cells red: signal transduction mediated by erythropoietin. Trends in cell biology 2005 Mar;15(3):146-55
  8. Kirito K, Uchida M, Yamada M, Miura Y, Komatsu N
    A distinct function of STAT proteins in erythropoietin signal transduction. The Journal of biological chemistry 1997 Jun 27;272(26):16507-13
  9. Kirito K, Nakajima K, Watanabe T, Uchida M, Tanaka M, Ozawa K, Komatsu N
    Identification of the human erythropoietin receptor region required for Stat1 and Stat3 activation. Blood 2002 Jan 1;99(1):102-10
  10. Kirito K, Nagashima T, Ozawa K, Komatsu N
    Constitutive activation of Stat1 and Stat3 in primary erythroleukemia cells. International journal of hematology 2002 Jan;75(1):51-4
  11. Ota J, Kimura F, Sato K, Wakimoto N, Nakamura Y, Nagata N, Suzu S, Yamada M, Shimamura S, Motoyoshi K
    Association of CrkL with STAT5 in hematopoietic cells stimulated by granulocyte-macrophage colony-stimulating factor or erythropoietin. Biochemical and biophysical research communications 1998 Nov 27;252(3):779-86
  12. 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
  13. Okutani Y, Kitanaka A, Tanaka T, Kamano H, Ohnishi H, Kubota Y, Ishida T, Takahara J
    Src directly tyrosine-phosphorylates STAT5 on its activation site and is involved in erythropoietin-induced signaling pathway. Oncogene 2001 Oct 4;20(45):6643-50
  14. Lacombe C, Mayeux P
    The molecular biology of erythropoietin. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 1999;14 Suppl 2:22-8
  15. Wei L, Han BH, Li Y, Keogh CL, Holtzman DM, Yu SP
    Cell death mechanism and protective effect of erythropoietin after focal ischemia in the whisker-barrel cortex of neonatal rats. The Journal of pharmacology and experimental therapeutics 2006 Apr;317(1):109-16
  16. Menon MP, Karur V, Bogacheva O, Bogachev O, Cuetara B, Wojchowski DM
    Signals for stress erythropoiesis are integrated via an erythropoietin receptor-phosphotyrosine-343-Stat5 axis. The Journal of clinical investigation 2006 Mar;116(3):683-94
  17. Zhang F, Wang S, Cao G, Gao Y, Chen J
    Signal transducers and activators of transcription 5 contributes to erythropoietin-mediated neuroprotection against hippocampal neuronal death after transient global cerebral ischemia. Neurobiology of disease 2007 Jan;25(1):45-53
  18. Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O
    Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood 1998 May 15;91(10):3734-45
  19. Kakihana K, Yamamoto M, Iiyama M, Miura O
    Calmodulin physically interacts with the erythropoietin receptor and enhances Jak2-mediated signaling. Biochemical and biophysical research communications 2005 Sep 23;335(2):424-31
  20. Tian X, Feig LA
    Basis for signaling specificity difference between Sos and Ras-GRF guanine nucleotide exchange factors. The Journal of biological chemistry 2001 Dec 14;276(50):47248-56
  21. Zhang J, Lodish HF
    Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors. Blood 2004 Sep 15;104(6):1679-87
  22. Wierenga AT, Vogelzang I, Eggen BJ, Vellenga E
    Erythropoietin-induced serine 727 phosphorylation of STAT3 in erythroid cells is mediated by a MEK-, ERK-, and MSK1-dependent pathway. Experimental hematology 2003 May;31(5):398-405
  23. Sangrar W, Gao Y, Bates B, Zirngibl R, Greer PA
    Activated Fps/Fes tyrosine kinase regulates erythroid differentiation and survival. Experimental hematology 2004 Oct;32(10):935-45
  24. Hortner M, Nielsch U, Mayr LM, Heinrich PC, Haan S
    A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor. European journal of biochemistry / FEBS 2002 May;269(10):2516-26
  25. Jegalian AG, Wu H
    Differential roles of SOCS family members in EpoR signal transduction. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 2002 Aug;22(8):853-60
  26. Cacalano NA, Sanden D, Johnston JA
    Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras. Nature cell biology 2001 May;3(5):460-5
  27. Wakioka T, Sasaki A, Mitsui K, Yokouchi M, Inoue A, Komiya S, Yoshimura A
    APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 1999 May;13(5):760-7
  28. Carter-Su C, Rui L, Stofega MR
    SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone. Recent progress in hormone research 2000;55:293-311
  29. Cheung JY, Miller BA
    Molecular mechanisms of erythropoietin signaling. Nephron 2001 Mar;87(3):215-22
  30. De Souza D, Fabri LJ, Nash A, Hilton DJ, Nicola NA, Baca M
    SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities. Biochemistry 2002 Jul 23;41(29):9229-36
  31. Minoo P, Zadeh MM, Rottapel R, Lebrun JJ, Ali S
    A novel SHP-1/Grb2-dependent mechanism of negative regulation of cytokine-receptor signaling: contribution of SHP-1 C-terminal tyrosines in cytokine signaling. Blood 2004 Feb 15;103(4):1398-407

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