Signal transduction - JNK pathway

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JNK pathway

The Mitogen-activated protein kinases 8-10 (JNK(MAPK8-10)) belong to a sub-group of evolutionarily conserved mitogen-activated protein kinases (MAPK) activated primarily by cytokines, growth factors and by exposure to environmental stress. JNK(MAPK8-10) activity is regulated through multi-tiered cascades composed of MAPK kinases (MAPKK, MKK or MEK) and MAPKK kinase or MEK kinase (MAPKKK or MEKK) [1]. Mitogen-activated protein kinase kinases 4 and 7 (MEK4(MAP2K4) and MKK7(MAP2K7)) are the specific MAPK kinase isoforms that activate JNK(MAPK8-10) [2], [3].

Tumor necrosis factor (TNF-alpha) signaling is a prominent activator of JNK(MAPK8-10) pathway. TNF-alpha binds and induces trimerization of Tumor necrosis factor receptor superfamily, member 1A (TNF-R1) and triggers its association with TNFRSF1A-associated via death domain (TRADD), that recruits TNF receptor-associated factor 2 (TRAF2). TRAF2 activates Mitogen-activated protein kinase kinase kinase kinases 2, 3, 4 and 5 (GCK(MAP4K2), GLK(MAP4K3), HGK(MAP4K4) and GCKR(MAP4K5)). These kinases, in turn, activate downstream kinases Mitogen-activated protein kinase kinase kinases 1, 7 and 11 (MEKK1(MAP3K1), TAK1(MAP3K7), MLK3(MAP3K11)). These kinases phosphorylate MEK4(MAP2K4) and MKK7(MAP2K7) that in turn activate JNK(MAPK8-10) [4], [5], [6], [7]. In addition, TRAF2 stimulates Mitogen-activated protein kinase kinase kinase 5 (ASK1(MAP3K5)) that can directly activate MEK4(MAP2K4) and MKK7(MAP2K7) followed by JNK(MAPK8-10) activation [8], [9].

Growth factors bind to and activate Growth factor receptors. The latter activate v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-RAS) via the growth factor receptor-bound protein 2 (GRB2)/ Son of sevenless homologs (SOS) pathway. H-RAS binds to and activates GCKR(MAP4K5) that in turn phosphorylates and activates MEKK1(MAP3K1). The latter phosphorylates and activates JNK(MAPK8-10) [10], [11]. In addition, H-RAS can suppress JNK(MAPK8-10) signaling by recruitment of the v-Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1). The latter inhibits ASK1(MAP3K5) and its downstream effector JNK(MAPK8-10) [12].

Growth factor signaling also promotes activation of the v-crk sarcoma virus CT10 oncogene homolog (CRK) that, via recruitment of Mitogen-activated protein kinase kinase kinase kinase 1 (HPK1(MAP4K1)), stimulates activity of MLK3(MAP3K11), MEKK1(MAP3K1) and TAK1(MAP3K7) and their downstream targets MEK4(MAP2K4) and MKK7(MAP2K7) thereby leading to activation of the JNK(MAPK8-10) [13], [14].

The Fas ligand (FasL(TNFSF6)) can activate JNK(MAPK8-10) pathway through induction of Fas (FasR(CD95)) association with Death-domain associated protein (DAXX) and subsequent activation of ASK1(MAP3K5)/ MEK4(MAP2K4) and MKK7(MAP2K7)/ JNK(MAPK8-10) [15], [16], [17], [18].

Small GTPases Ras-related C3 botulinum toxin substrate 1 (Rac1) and Cell division cycle 42 (CDC42) can activate the JNK(MAPK8-10) pathway by binding and stimulating the Mitogen-activated protein kinase kinase kinases 4 and 10 (MEKK4(MAP3K4), MLK2(MAP3K10)), MLK3(MAP3K11) and MEKK1(MAP3K1) These kinases phosphorylate MEK4(MAP2K4) and MKK7(MAP2K7) followed by JNK(MAPK8-10) activation [19], [20], [21].

Some protein kinases, including Mitogen-activated protein kinase kinase kinases 2, 3, 8, 12 and 13 (MAP3K2(MEKK2), MAP3K3, TPL2(MAP3K8), ZPK(MAP3K12) and LZK(MAP3K13)) can also promote JNK(MAPK8-10) signaling via phosphorylation and activation of MEK4(MAP2K4) and MKK7(MAP2K7) [21], [22], [23], [24], [25], [26].

Activated JNK(MAPK8-10) kinases regulate gene expression by phosphorylating a wide variety of nuclear targets. First of all, they activate AP-1 family of transcription factors, including Jun oncogene (c-Jun), Jun D proto-oncogene (JunD) and Activating transcription factor 2 (ATF-2) [2], [27]. In addition, they stimulate ELK1 member of ETS oncogene family (Elk-1) and ELK4 ETS-domain protein (Elk-4) transcriptional activity [27], [28], [29]. JNK(MAPK8-10) kinases also phosphorylate and activate Tumor protein p53 (p53). Besides, JNK(MAPK8-10) can negatively regulate Nuclear factors of activated T-cells, cytoplasmic, calcineurin-dependent 1 and 3 (NF-AT2(NFATC1), NF-AT4(NFATC3)) activity [27], [30].

References:

  1. Chang L, Karin M
    Mammalian MAP kinase signalling cascades. Nature 2001 Mar 1;410(6824):37-40
  2. Davis RJ
    Signal transduction by the JNK group of MAP kinases. Cell 2000 Oct 13;103(2):239-52
  3. Wang X, Destrument A, Tournier C
    Physiological roles of MKK4 and MKK7: insights from animal models. Biochimica et biophysica acta 2007 Aug;1773(8):1349-57
  4. Shi CS, Kehrl JH
    Activation of stress-activated protein kinase/c-Jun N-terminal kinase, but not NF-kappaB, by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor 2- and germinal center kinase related-dependent pathway. The Journal of biological chemistry 1997 Dec 19;272(51):32102-7
  5. Yuasa T, Ohno S, Kehrl JH, Kyriakis JM
    Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. The Journal of biological chemistry 1998 Aug 28;273(35):22681-92
  6. Yao Z, Zhou G, Wang XS, Brown A, Diener K, Gan H, Tan TH
    A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. The Journal of biological chemistry 1999 Jan 22;274(4):2118-25
  7. Shi CS, Leonardi A, Kyriakis J, Siebenlist U, Kehrl JH
    TNF-mediated activation of the stress-activated protein kinase pathway: TNF receptor-associated factor 2 recruits and activates germinal center kinase related. Journal of immunology (Baltimore, Md. : 1950) 1999 Sep 15;163(6):3279-85
  8. Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y
    Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science (New York, N.Y.) 1997 Jan 3;275(5296):90-4
  9. Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H
    ASK1 is essential for JNK/SAPK activation by TRAF2. Molecular cell 1998 Sep;2(3):389-95
  10. Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ
    JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 1994 Mar 25;76(6):1025-37
  11. Shi CS, Tuscano JM, Witte ON, Kehrl JH
    GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway. Blood 1999 Feb 15;93(4):1338-45
  12. Baccarini M
    Second nature: biological functions of the Raf-1 "kinase". FEBS letters 2005 Jun 13;579(15):3271-7
  13. Dolfi F, Garcia-Guzman M, Ojaniemi M, Nakamura H, Matsuda M, Vuori K
    The adaptor protein Crk connects multiple cellular stimuli to the JNK signaling pathway. Proceedings of the National Academy of Sciences of the United States of America 1998 Dec 22;95(26):15394-9
  14. Ling P, Yao Z, Meyer CF, Wang XS, Oehrl W, Feller SM, Tan TH
    Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase. Molecular and cellular biology 1999 Feb;19(2):1359-68
  15. Yang X, Khosravi-Far R, Chang HY, Baltimore D
    Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 1997 Jun 27;89(7):1067-76
  16. Chang HY, Nishitoh H, Yang X, Ichijo H, Baltimore D
    Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science (New York, N.Y.) 1998 Sep 18;281(5384):1860-3
  17. Wajant H
    The Fas signaling pathway: more than a paradigm. Science (New York, N.Y.) 2002 May 31;296(5573):1635-6
  18. Khelifi AF, D'Alcontres MS, Salomoni P
    Daxx is required for stress-induced cell death and JNK activation. Cell death and differentiation 2005 Jul;12(7):724-33
  19. Teramoto H, Coso OA, Miyata H, Igishi T, Miki T, Gutkind JS
    Signaling from the small GTP-binding proteins Rac1 and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. The Journal of biological chemistry 1996 Nov 1;271(44):27225-8
  20. Nagata K, Puls A, Futter C, Aspenstrom P, Schaefer E, Nakata T, Hirokawa N, Hall A
    The MAP kinase kinase kinase MLK2 co-localizes with activated JNK along microtubules and associates with kinesin superfamily motor KIF3. The EMBO journal 1998 Jan 2;17(1):149-58
  21. Hagemann C, Blank JL
    The ups and downs of MEK kinase interactions. Cellular signalling 2001 Dec;13(12):863-75
  22. Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC
    Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. The EMBO journal 1996 Feb 15;15(4):817-26
  23. Hirai S, Izawa M, Osada S, Spyrou G, Ohno S
    Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK. Oncogene 1996 Feb 1;12(3):641-50
  24. Merritt SE, Mata M, Nihalani D, Zhu C, Hu X, Holzman LB
    The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate. The Journal of biological chemistry 1999 Apr 9;274(15):10195-202
  25. Ikeda A, Masaki M, Kozutsumi Y, Oka S, Kawasaki T
    Identification and characterization of functional domains in a mixed lineage kinase LZK. FEBS letters 2001 Jan 19;488(3):190-5
  26. Ikeda A, Hasegawa K, Masaki M, Moriguchi T, Nishida E, Kozutsumi Y, Oka S, Kawasaki T
    Mixed lineage kinase LZK forms a functional signaling complex with JIP-1, a scaffold protein of the c-Jun NH(2)-terminal kinase pathway. Journal of biochemistry 2001 Dec;130(6):773-81
  27. Bogoyevitch MA, Kobe B
    Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases. Microbiology and molecular biology reviews : MMBR 2006 Dec;70(4):1061-95
  28. Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B, Davis RJ
    Selective interaction of JNK protein kinase isoforms with transcription factors. The EMBO journal 1996 Jun 3;15(11):2760-70
  29. Janknecht R, Hunter T
    Activation of the Sap-1a transcription factor by the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase. The Journal of biological chemistry 1997 Feb 14;272(7):4219-24
  30. Chow CW, Rincon M, Cavanagh J, Dickens M, Davis RJ
    Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. Science (New York, N.Y.) 1997 Nov 28;278(5343):1638-41

  1. Chang L, Karin M
    Mammalian MAP kinase signalling cascades. Nature 2001 Mar 1;410(6824):37-40
  2. Davis RJ
    Signal transduction by the JNK group of MAP kinases. Cell 2000 Oct 13;103(2):239-52
  3. Wang X, Destrument A, Tournier C
    Physiological roles of MKK4 and MKK7: insights from animal models. Biochimica et biophysica acta 2007 Aug;1773(8):1349-57
  4. Shi CS, Kehrl JH
    Activation of stress-activated protein kinase/c-Jun N-terminal kinase, but not NF-kappaB, by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor 2- and germinal center kinase related-dependent pathway. The Journal of biological chemistry 1997 Dec 19;272(51):32102-7
  5. Yuasa T, Ohno S, Kehrl JH, Kyriakis JM
    Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. The Journal of biological chemistry 1998 Aug 28;273(35):22681-92
  6. Yao Z, Zhou G, Wang XS, Brown A, Diener K, Gan H, Tan TH
    A novel human STE20-related protein kinase, HGK, that specifically activates the c-Jun N-terminal kinase signaling pathway. The Journal of biological chemistry 1999 Jan 22;274(4):2118-25
  7. Shi CS, Leonardi A, Kyriakis J, Siebenlist U, Kehrl JH
    TNF-mediated activation of the stress-activated protein kinase pathway: TNF receptor-associated factor 2 recruits and activates germinal center kinase related. Journal of immunology (Baltimore, Md. : 1950) 1999 Sep 15;163(6):3279-85
  8. Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y
    Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science (New York, N.Y.) 1997 Jan 3;275(5296):90-4
  9. Nishitoh H, Saitoh M, Mochida Y, Takeda K, Nakano H, Rothe M, Miyazono K, Ichijo H
    ASK1 is essential for JNK/SAPK activation by TRAF2. Molecular cell 1998 Sep;2(3):389-95
  10. Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Karin M, Davis RJ
    JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 1994 Mar 25;76(6):1025-37
  11. Shi CS, Tuscano JM, Witte ON, Kehrl JH
    GCKR links the Bcr-Abl oncogene and Ras to the stress-activated protein kinase pathway. Blood 1999 Feb 15;93(4):1338-45
  12. Baccarini M
    Second nature: biological functions of the Raf-1 "kinase". FEBS letters 2005 Jun 13;579(15):3271-7
  13. Dolfi F, Garcia-Guzman M, Ojaniemi M, Nakamura H, Matsuda M, Vuori K
    The adaptor protein Crk connects multiple cellular stimuli to the JNK signaling pathway. Proceedings of the National Academy of Sciences of the United States of America 1998 Dec 22;95(26):15394-9
  14. Ling P, Yao Z, Meyer CF, Wang XS, Oehrl W, Feller SM, Tan TH
    Interaction of hematopoietic progenitor kinase 1 with adapter proteins Crk and CrkL leads to synergistic activation of c-Jun N-terminal kinase. Molecular and cellular biology 1999 Feb;19(2):1359-68
  15. Yang X, Khosravi-Far R, Chang HY, Baltimore D
    Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 1997 Jun 27;89(7):1067-76
  16. Chang HY, Nishitoh H, Yang X, Ichijo H, Baltimore D
    Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science (New York, N.Y.) 1998 Sep 18;281(5384):1860-3
  17. Wajant H
    The Fas signaling pathway: more than a paradigm. Science (New York, N.Y.) 2002 May 31;296(5573):1635-6
  18. Khelifi AF, D'Alcontres MS, Salomoni P
    Daxx is required for stress-induced cell death and JNK activation. Cell death and differentiation 2005 Jul;12(7):724-33
  19. Teramoto H, Coso OA, Miyata H, Igishi T, Miki T, Gutkind JS
    Signaling from the small GTP-binding proteins Rac1 and Cdc42 to the c-Jun N-terminal kinase/stress-activated protein kinase pathway. A role for mixed lineage kinase 3/protein-tyrosine kinase 1, a novel member of the mixed lineage kinase family. The Journal of biological chemistry 1996 Nov 1;271(44):27225-8
  20. Nagata K, Puls A, Futter C, Aspenstrom P, Schaefer E, Nakata T, Hirokawa N, Hall A
    The MAP kinase kinase kinase MLK2 co-localizes with activated JNK along microtubules and associates with kinesin superfamily motor KIF3. The EMBO journal 1998 Jan 2;17(1):149-58
  21. Hagemann C, Blank JL
    The ups and downs of MEK kinase interactions. Cellular signalling 2001 Dec;13(12):863-75
  22. Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC
    Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. The EMBO journal 1996 Feb 15;15(4):817-26
  23. Hirai S, Izawa M, Osada S, Spyrou G, Ohno S
    Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK. Oncogene 1996 Feb 1;12(3):641-50
  24. Merritt SE, Mata M, Nihalani D, Zhu C, Hu X, Holzman LB
    The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate. The Journal of biological chemistry 1999 Apr 9;274(15):10195-202
  25. Ikeda A, Masaki M, Kozutsumi Y, Oka S, Kawasaki T
    Identification and characterization of functional domains in a mixed lineage kinase LZK. FEBS letters 2001 Jan 19;488(3):190-5
  26. Ikeda A, Hasegawa K, Masaki M, Moriguchi T, Nishida E, Kozutsumi Y, Oka S, Kawasaki T
    Mixed lineage kinase LZK forms a functional signaling complex with JIP-1, a scaffold protein of the c-Jun NH(2)-terminal kinase pathway. Journal of biochemistry 2001 Dec;130(6):773-81
  27. Bogoyevitch MA, Kobe B
    Uses for JNK: the many and varied substrates of the c-Jun N-terminal kinases. Microbiology and molecular biology reviews : MMBR 2006 Dec;70(4):1061-95
  28. Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK, Derijard B, Davis RJ
    Selective interaction of JNK protein kinase isoforms with transcription factors. The EMBO journal 1996 Jun 3;15(11):2760-70
  29. Janknecht R, Hunter T
    Activation of the Sap-1a transcription factor by the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase. The Journal of biological chemistry 1997 Feb 14;272(7):4219-24
  30. Chow CW, Rincon M, Cavanagh J, Dickens M, Davis RJ
    Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. Science (New York, N.Y.) 1997 Nov 28;278(5343):1638-41

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