Signal transduction - Erk Interactions: Inhibition of Erk

Erk Interactions: Inhibition of Erk

Mitogen-activated protein kinase (MAPK) pathways regulate a variety of physiological processes, such as cell growth, differentiation, and apoptotic cell death. To date, three MAPK pathways have been characterized in detail. The extracellular regulated kinase (ERK) pathway is activated by a large variety of mitogens and growth factors, whereas the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and p38 pathways are stimulated mainly by environmental stress and inflammatory cytokines. The ERK pathway, which includes the regulation and signaling cascade of Mitogen-activated protein kinases 3 and 1 (ERK1/2), is involved in cell growth, proliferation and survival [1].

Reversible phosphorylation of MAPK proteins emphasizes the importance of balance between the phosphorylating kinases and dephosphorylating phosphatases in regulating these pathways. In general, dephosphorylation of MAPKs decreases their kinase activity that is essential for cell to remain responsive to stimuli and to prevent deleterious effects of prolonged pathway stimulation [1], [2].

ERK pathway phosphatases are classified according to their substrate specificities into dual-specificity MAPK phosphatases, protein serine/threonine phosphatases, and protein tyrosine phosphatases. In addition, two different families of phosphatases can cooperate in complex to regulate ERK1/2 dephosphorylation. A cholesterol-regulated Protein phosphatase 2A (PP2A catalytic)/ Protein tyrosine phosphatase, non-receptor type 7 (HePTP) complex dephosphorylates both the phosphotyrosine and the phosphothreonine residues in the activation loop of ERK1/2 due to the combined activities of the serine/threonine phosphatase PP2A catalytic and the tyrosine phosphatase HePTP [3].

PP2A catalytic dephosphorylates and blocks activation of both ERK1/2 and its upstream kinase, Mitogen-activated protein kinase kinase 1 (MEK1(MAP2K1)), determining the kinetics of MAPK cascades [4], [5].

HePTP inactivates ERK1/2 by dephosphorylating the critical phosphorylated tyrosine residue in their activation loop. Cyclic-AMP-dependent protein kinase (composed of regulatory PKA-reg (cAMP-dependent) and catalytic PKA-cat (cAMP-dependent) subunits) phosphorylates HePTP reducing its binding to ERK1/2 which causes ERK1/2 release and activation [6].

Protein tyrosine phosphatase receptor type (RPTPRR) and Protein tyrosine phosphatase non-receptor type 5 (STEP) retain ERK1/2 in the cytoplasm in an inactive form by association through a kinase interaction motif and tyrosine dephosphorylation. Phosphorylation of RPTPRR and STEP by PKA-cat (cAMP-dependent) suppresses their association with ERK1/2 and favors ERK1/2 activation and translocation to the nucleus [7], [8], [9].

In neurons, activation of NMDA receptors leads to activation of STEP, which limited the duration of ERK1/2 activity as well as its translocation to the nucleus and its subsequent downstream nuclear signaling. NMDA-mediated influx of Ca(2+) leads to activation of the Ca(2+)/ Calmodulin-dependent phosphatase Calcineurin A (catalytic) that dephosphorylates and activates STEP [10].

Protein tyrosine phosphatase receptor type E (PTPR-epsilon) is also a physiological inhibitor of ERK signaling by protecting cells from prolonged ERK1/2 activation in the cytosol [11].

Glia maturation factor beta (GMF) is an inhibitor of ERK1/2, and phosphorylation of GMF by PKA-cat (cAMP-dependent) dramatically increases its inhibitory effect [12].

Dual-specificity phosphatases (such as MKP-1, MKP-2, MKP-3, MKP-4, MKP-7 and MKP-X) dephosphorylate both phosphotyrosine and phosphothreonine residues on ERK1/2 [1], [2], [13]. Regulation of MKP activity includes ERK1/2-dependent feedback mechanism for activation phosphatase function [1], [14], [15], [16]. For example, ERK1/2 can phosphorylate MKP-1 and MKP-2 and prevent their degradation by inhibiting ubiquitination [15], [17].

MKP-1 and MKP-7 can also dephosphorylate and inactivate Mitogen-activated protein kinases 8-10 (JNK(MAPK8-10)), changing the levels of signaling through multiple MAPK pathways [18], [19], [20], [21].

T cell receptor (TCR alpha/beta)-CD3 complex also plays an important role in regulating ERK pathways in T cells. In TCR signaling, Zeta-chain (TCR) associated protein kinase 70kDa (ZAP70) is phosphorylated and activated by lymphocyte-specific protein tyrosine kinase (Lck), leading to the activation of ERK pathway [22], [23], [24]. Dual specificity phosphatase 3 (VHR) accumulates at the T cell/ Antigen presenting cell (APC) contact site, where it is phosphorylated by ZAP70. This phosphorylation is required for VHR to inhibit ERK1/2, giving ZAP70 an unanticipated control over ERK signaling pathway, in addition to its role as upstream activator of the Ras/Raf/MEK/ERK pathway [25], [26].

VHR is a constitutively expressed tyrosine-specific phosphatase which specifically dephosphorylates and inactivates ERK1/2 in the nucleus [27]. Vaccinia related kinase 3 (VRK3) suppresses ERK1/2 activity through direct binding to VHR. VRK3 enhances the phosphatase activity of VHR by a mechanism independent of its kinase activity, [28], [29].

ERK1/2 activity is also regulated by its subcellular localization, which can be controlled by Phosphoprotein enriched in astrocytes 15 (PEA-15). PEA-15 directly binds to and sequesters ERK1/2 in the cytoplasm thereby preventing ERK1/2 access to nuclear targets [30], [31], [32], [33]. Phosphorylation of PEA-15 by Calcium/calmodulin-dependent protein kinase II (CaMK II), Protein kinase C (PKC) and v-Akt murine thymoma viral oncogene homolog (AKT) blocks its interaction with ERK1/2 and abrogates its capacity to prevent the nuclear localization of ERK1/2 [34].

References:

1. Junttila MR, Li SP, Westermarck J
   Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2008 Apr;22(4):954-65
2. Keyse SM
   Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer metastasis reviews 2008 Jun;27(2):253-61
3. Wang PY, Liu P, Weng J, Sontag E, Anderson RG
   A cholesterol-regulated PP2A/HePTP complex with dual specificity ERK1/2 phosphatase activity. The EMBO journal 2003 Jun 2;22(11):2658-67
4. Millward TA, Zolnierowicz S, Hemmings BA
   Regulation of protein kinase cascades by protein phosphatase 2A. Trends in biochemical sciences 1999 May;24(5):186-91
5. Liu Q, Hofmann PA
   Protein phosphatase 2A-mediated cross-talk between p38 MAPK and ERK in apoptosis of cardiac myocytes. American journal of physiology. Heart and circulatory physiology 2004 Jun;286(6):H2204-12
6. Saxena M, Williams S, Tasken K, Mustelin T
   Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphatase. Nature cell biology 1999 Sep;1(5):305-11
7. Pulido R, Zu?iga A, Ullrich A
   PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. The EMBO journal 1998 Dec 15;17(24):7337-50
8. Zu?iga A, Torres J, Ubeda J, Pulido R
   Interaction of mitogen-activated protein kinases with the kinase interaction motif of the tyrosine phosphatase PTP-SL provides substrate specificity and retains ERK2 in the cytoplasm. The Journal of biological chemistry 1999 Jul 30;274(31):21900-7
9. Blanco-Aparicio C, Torres J, Pulido R
   A novel regulatory mechanism of MAP kinases activation and nuclear translocation mediated by PKA and the PTP-SL tyrosine phosphatase. The Journal of cell biology 1999 Dec 13;147(6):1129-36
10. Paul S, Nairn AC, Wang P, Lombroso PJ
    NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling. Nature neuroscience 2003 Jan;6(1):34-42
11. Toledano-Katchalski H, Kraut J, Sines T, Granot-Attas S, Shohat G, Gil-Henn H, Yung Y, Elson A
    Protein tyrosine phosphatase epsilon inhibits signaling by mitogen-activated protein kinases. Molecular cancer research : MCR 2003 May;1(7):541-50
12. Zaheer A, Lim R
    In vitro inhibition of MAP kinase (ERK1/ERK2) activity by phosphorylated glia maturation factor (GMF). Biochemistry 1996 May 21;35(20):6283-8
13. Owens DM, Keyse SM
    Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 2007 May 14;26(22):3203-13
14. Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, Chabert C, Boschert U, Arkinstall S
    Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science (New York, N.Y.) 1998 May 22;280(5367):1262-5
15. Pouyssegur J, Lenormand P
    Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. European journal of biochemistry / FEBS 2003 Aug;270(16):3291-9
16. Ramos JW
    The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells. The international journal of biochemistry & cell biology 2008;40(12):2707-19
17. Brondello JM, Pouyssegur J, McKenzie FR
    Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science (New York, N.Y.) 1999 Dec 24;286(5449):2514-7
18. Franklin CC, Kraft AS
    Conditional expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1 preferentially inhibits p38 MAPK and stress-activated protein kinase in U937 cells. The Journal of biological chemistry 1997 Jul 4;272(27):16917-23
19. Masuda K, Shima H, Katagiri C, Kikuchi K
    Activation of ERK induces phosphorylation of MAPK phosphatase-7, a JNK specific phosphatase, at Ser-446. The Journal of biological chemistry 2003 Aug 22;278(34):32448-56
20. Dickinson RJ, Keyse SM
    Diverse physiological functions for dual-specificity MAP kinase phosphatases. Journal of cell science 2006 Nov 15;119(Pt 22):4607-15
21. Hou N, Torii S, Saito N, Hosaka M, Takeuchi T
    Reactive oxygen species-mediated pancreatic beta-cell death is regulated by interactions between stress-activated protein kinases, p38 and c-Jun N-terminal kinase, and mitogen-activated protein kinase phosphatases. Endocrinology 2008 Apr;149(4):1654-65
22. Pacini S, Ulivieri C, Di Somma MM, Isacchi A, Lanfrancone L, Pelicci PG, Telford JL, Baldari CT
    Tyrosine 474 of ZAP-70 is required for association with the Shc adaptor and for T-cell antigen receptor-dependent gene activation. The Journal of biological chemistry 1998 Aug 7;273(32):20487-93
23. Visco C, Magistrelli G, Bosotti R, Perego R, Rusconi L, Toma S, Zamai M, Acuto O, Isacchi A
    Activation of Zap-70 tyrosine kinase due to a structural rearrangement induced by tyrosine phosphorylation and/or ITAM binding. Biochemistry 2000 Mar 14;39(10):2784-91
24. Werlen G, Hausmann B, Palmer E
    A motif in the alphabeta T-cell receptor controls positive selection by modulating ERK activity. Nature 2000 Jul 27;406(6794):422-6
25. Alonso A, Saxena M, Williams S, Mustelin T
    Inhibitory role for dual specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. The Journal of biological chemistry 2001 Feb 16;276(7):4766-71
26. Alonso A, Rahmouni S, Williams S, van Stipdonk M, Jaroszewski L, Godzik A, Abraham RT, Schoenberger SP, Mustelin T
    Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nature immunology 2003 Jan;4(1):44-8
27. Todd JL, Tanner KG, Denu JM
    Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway. The Journal of biological chemistry 1999 May 7;274(19):13271-80
28. Kang TH, Kim KT
    Negative regulation of ERK activity by VRK3-mediated activation of VHR phosphatase. Nature cell biology 2006 Aug;8(8):863-9
29. Kang TH, Kim KT
    VRK3-mediated inactivation of ERK signaling in adult and embryonic rodent tissues. Biochimica et biophysica acta 2008 Jan;1783(1):49-58
30. Whitehurst AW, Robinson FL, Moore MS, Cobb MH
    The death effector domain protein PEA-15 prevents nuclear entry of ERK2 by inhibiting required interactions. The Journal of biological chemistry 2004 Mar 26;279(13):12840-7
31. Chou FL, Hill JM, Hsieh JC, Pouyssegur J, Brunet A, Glading A, Uberall F, Ramos JW, Werner MH, Ginsberg MH
    PEA-15 binding to ERK1/2 MAPKs is required for its modulation of integrin activation. The Journal of biological chemistry 2003 Dec 26;278(52):52587-97
32. Gaumont-Leclerc MF, Mukhopadhyay UK, Goumard S, Ferbeyre G
    PEA-15 is inhibited by adenovirus E1A and plays a role in ERK nuclear export and Ras-induced senescence. The Journal of biological chemistry 2004 Nov 5;279(45):46802-9
33. Glading A, Koziol JA, Krueger J, Ginsberg MH
    PEA-15 inhibits tumor cell invasion by binding to extracellular signal-regulated kinase 1/2. Cancer research 2007 Feb 15;67(4):1536-44
34. Krueger J, Chou FL, Glading A, Schaefer E, Ginsberg MH
    Phosphorylation of phosphoprotein enriched in astrocytes (PEA-15) regulates extracellular signal-regulated kinase-dependent transcription and cell proliferation. Molecular biology of the cell 2005 Aug;16(8):3552-61