Your browser does not support JavaScript!
http://iet.metastore.ingenta.com
1887

Sensitivity analysis predicts that the ERK–pMEK interaction regulates ERK nuclear translocation

Sensitivity analysis predicts that the ERK–pMEK interaction regulates ERK nuclear translocation

For access to this article, please select a purchase option:

Buy article PDF
£12.50
(plus tax if applicable)
Add to cart
Buy Knowledge Pack
10 articles for £75.00
(plus taxes if applicable)
Add to cart

IET members benefit from discounts to all IET publications and free access to E&T Magazine. If you are an IET member, log in to your account and the discounts will automatically be applied.

Learn more about IET membership 

Recommend Title Publication to library

You must fill out fields marked with: *

Librarian details
Name:*
Email:*
Your details
Name:*
Email:*
Department:*
Why are you recommending this title?
Select reason:
 
 
 
 
 
IET Systems Biology — Recommend this title to your library

Thank you

Your recommendation has been sent to your librarian.

© The Institution of Engineering and Technology
Published

Following phosphorylation, nuclear translocation of the mitogen-activated protein kinases (MAPKs), ERK1 and ERK2, is critical for both gene expression and DNA replication induced by growth factors. ERK nuclear translocation has therefore been studied extensively, but many details remain unresolved, including whether or not ERK dimerisation is required for translocation. Here, we simulate ERK nuclear translocation with a compartmental computational model that includes systematic sensitivity analysis. The governing ordinary differential equations are solved with the backward differentiation formula and decoupled direct methods. To better understand the regulation of ERK nuclear translocation, we use this model in conjunction with a previously published model of the ERK pathway that does not include an ERK dimer species and with experimental measurements of nuclear translocation of wild-type ERK and a mutant form, ERK1-Δ4, which is unable to dimerise. Sensitivity analysis reveals that the delayed nuclear uptake of ERK1-Δ4 compared to that of wild-type ERK1 can be explained by the altered interaction of ERK1-Δ4 with phosphorylated MEK (MAPK/ERK kinase), and so may be independent of dimerisation. Our study also identifies biological experiments that can verify this explanation.

Inspec keywords: molecular biophysics; sensitivity analysis; genetics; DNA; proteins; cellular biophysics; differential equations; biochemistry

Other keywords: wild-type ERK pathway; ordinary differential equations; ERK dimerisation; ERK-pMEK interaction regulation; phosphorylation; systematic sensitivity analysis; ERK2; sensitivity analysis prediction; DNA replication; gene expression; mitogen-activated protein kinases; ERK dimer species; ERK1; extracellular signal-regulated kinase 2; delayed nuclear uptake; ERK nuclear translocation; extracellular signal-regulated kinase 1

Subjects: Biomolecular interactions, charge transfer complexes; Macromolecular constitution (chains and sequences); Macromolecular conformation (statistics and dynamics); Biomolecular dynamics, molecular probes, molecular pattern recognition; Physical chemistry of biomolecular solutions and condensed states; Physics of subcellular structures; Function theory, analysis; Macromolecular configuration (bonds, dimensions); Biomolecular structure, configuration, conformation, and active sites

References

    1. 1)
      • A.M. Dunker . The decoupled direct method for calculating sensitivity coefficients in chemical kinetics. J. Chem. Phys. , 2385 - 2393
    2. 2)
      • H.S. Wiley , S.Y. Shvartsman , D.A. Lauffenburger . Computational modeling of the EGF-receptor system: a paradigm for systems biology. Trends Cell Biol. , 43 - 50
    3. 3)
      • K.R. Chien , M. Hoshijima . Unravelling Ras signals in cardiovascular disease. Nat. Cell Biol. , 807 - 808
    4. 4)
      • E.R. Butch , K.-L. Guan . Characterization of ERK1 activation site mutants and the effect on recognition by MEK1 and MEK2. J. Biol. Chem. , 4230 - 4235
    5. 5)
      • M.A. Puchowicz , K. Radhakrishnan , K. Xu , D.L. Magness , J.C. LaManna . Computational study on use of single-point analysis method for quantitating local cerebral blood flow in mice. Adv. Exp. Med. Biol. , 99 - 104
    6. 6)
      • P.M. Frank . (1978) Introduction to system sensitivity theory.
    7. 7)
      • M.J. Robinson , M. Cheng , A. Khokhlatchev . Contributions of the mitogen-activated protein (MAP) kinase backbone and phosphorylation loop to MEK specificity. J. Biol. Chem. , 29734 - 29739
    8. 8)
      • J. Hornberg , B. Bernd , F.J. Bruggeman , B. Schoeberl , R. Heinrich , H.V. Westerhoff . Control of MAPK signaling: from complexity to what really matters. Oncogene , 5533 - 5542
    9. 9)
      • R. Philipova , M. Whitaker . Active ERK1 is dimerized in vivo: bisphosphodimers generate peak kinase activity and monophosphodimers maintain basal ERK1 activitiy. J. Cell Sci. , 5767 - 5776
    10. 10)
      • T. Furuno , N. Hirashima , S. Onizawa , N. Sagiya , M. Nakanishi . Nuclear shuttling of mitogen-activated protein (MAP) kinase (extracellular signal-related kinase (ERK) 2) was dynamically controlled by MAP/ERK kinase after antigen stimulation in RBL-2H3 cells. J. Immunol. , 4416 - 4421
    11. 11)
      • K. Radhakrishnan , E.S. Oran , J.P. Boris . (1991) Combustion kinetics and sensitivity analysis computations, Numerical approaches to combustion modeling.
    12. 12)
      • T. Force , K. Kuida , M. Namchuk , K. Parang , J.M. Kyriakis . Inhibitors of protein kinase signaling pathways. Emerging therapies for cardiovascular disease. Circulation , 1196 - 1205
    13. 13)
      • B. Schoeberl , C. Eichler-Jonsson , E.D. Gilles , G. Müller . Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors. Nat. Biotech. , 370 - 375
    14. 14)
      • I. Wolf , H. Rubinfeld , S. Yoon , G. Marmor , T. Hanoch , R. Seger . Involvement of the activation loop of ERK in the detachment from cytosolic anchoring. J. Biol. Chem. , 24490 - 24497
    15. 15)
      • B.N. Kholodenko , O.V. Demin , G. Moehren , J.B. Hoek . Quantification of short term signaling by the epidermal growth factor receptor. J. Biol. Chem. , 30169 - 30181
    16. 16)
      • http://www.jbc.org/cgi/content/full/M509344200/DC1.
    17. 17)
      • A.V. Khokhlatchev , B. Canagarajah , J. Wilsbacher . Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation. Cell , 605 - 615
    18. 18)
      • K. Radhakrishnan , R. Vichnevetsky , R.S. Stepleman . (1987) Decoupled direct method for sensitivity analysis in combustion kinetics, Advances in computer methods for partial differential equations – VI.
    19. 19)
      • K. Radhakrishnan . LSENS–A general chemical kinetics and sensitivity analysis code for homogeneous gas-phase reactions. I. Theory and numerical solution procedures.
    20. 20)
      • M. Hatakeyama , S. Kimura , T. Naka . A computational model on the modulation of mitogen-activated protein kinase (MAPK) and Akt pathways in heregulin-induced ErbB signalling. Biochem. J. , 451 - 463
    21. 21)
      • R.J. Orton , O.E. Sturm , V. Vyshemirsky , M. Calder , D.R. Gilbert , W. Kolch . Computational modeling of the receptor-tyrosine-kinase activated MAPK pathway. Biochem. J. , 249 - 261
    22. 22)
      • K. Radhakrishnan . New integration techniques for chemical kinetic rate equations. I. Efficiency comparison. Combust. Sci. Tech. , 59 - 82
    23. 23)
      • S. Sasagawa , Y. Ozaki , K. Fujita , S. Kuroda . Prediction and validation of the distinct dynamics of transient and sustained ERK activation. Nat. Cell Biol. , 365 - 373
    24. 24)
      • G. Liu , M.T. Swihart , S. Neelameghan . Sensitivity, principal component and flux analysis applied to signal transduction: the case of epidermal growth factor mediated signaling. Bioinformatics , 1194 - 1202
    25. 25)
      • K. Radhakrishnan , A.C. Hindmarsh . Description and use of LSODE, the Livermore solver for ordinary differential equations.
    26. 26)
      • K. Radhakrishnan , D.A. Bittker . LSENS–A general chemical kinetics and sensitivity analysis code for homogeneous gas-phase reactions. II. Code description and usage.
    27. 27)
      • W.R. Burack , A.S. Shaw . Live cell imaging of ERK and MEK. Simple binding equilibrium explains the regulated nucleocytoplasmic distribution of ERK. J. Biol. Chem. , 3832 - 3837
    28. 28)
      • A.C. Hindmarsh . LSODE and LSODI, two new initial value ordinary differential equation solvers. ACM SIGNUM Newsl. , 10 - 11
    29. 29)
      • M.N. Yazicioglu , D.L. Goad , A. Ranganathan , A.W. Whitehurst , E.J. Goldsmith , M.H. Cobb . Mutations in ERK2 binding sites affect nuclear entry. J. Biol. Chem. , 28759 - 28767
    30. 30)
      • M. Fukuda , Y. Gotoh , E. Nishida . Interaction of MAP kinase with MAP kinase kinase: its possible role in the control of nucleocytoplasmic transport of MAP kinase. EMBO J. , 1901 - 1908
    31. 31)
      • A.M. Horgan , J.S. Stork . Examining the mechanism of ERK nuclear translocation using green fluorescent protein. Expt. Cell Res. , 208 - 220
    32. 32)
      • K. Radhakrishnan . A critical analysis of the accuracy of several numerical techniques for combustion kinetic rate equations.
    33. 33)
      • M.M. McKay , D.K. Morrison . Integrating signals from RTKs to ERK/MAPK. Oncogene , 3113 - 3121
    34. 34)
      • A. Fujioka , K. Terai , R.E. Itoh . Dynamics of the Ras/ERK MAPK cascade as monitored by fluorescent probes. J. Biol. Chem. , 8917 - 8926
    35. 35)
      • M. Costa , M. Marchi , F. Cardarelli . Dynamic regulation of ERK2 nuclear translocation and mobility in living cells. J. Cell Sci. , 4952 - 4963
    36. 36)
      • K. Radhakrishnan . New integration techniques for chemical kinetic rate equations. II. Accuracy comparison. J. Eng. Gas Turbines Power , 348 - 353
    37. 37)
      • M.C. Lawrence , A. Jivan , C. Shao . The roles of MAPKs in disease. Cell Res. , 436 - 442
    38. 38)
      • K. Radhakrishnan , J.C. LaManna , M.E. Cabrera . A quantitative study of oxygen as a metabolic regulator. Appl. Cardiopulmonary Pathophysiology , 363 - 367
    39. 39)
      • P. Lenormand , J.-M. Brondello , A. Brunet , J. Pouysségur . Growth factor-induced p42/p44 MAPK nuclear translocation and retention requires both MAPK activation and neosynthesis of nuclear anchoring proteins. J. Cell Biol. , 625 - 633
    40. 40)
      • M. Adachi , M. Fukuda , E. Nishida . Two co-existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimer. EMBO J. , 5347 - 5358
    41. 41)
      • Y. Zhang , C. Dong . Regulatory mechanisms of mitogen-activated kinase signaling. Cell. Mol. Life Sci. , 2771 - 2789
    42. 42)
      • C. Widmann , S. Gibson , M.B. Jarpe , G.L. Johnson . Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol. Rev. , 143 - 179
    43. 43)
      • M. Raman , W. Chen , M.H. Cobb . Differential regulation and properties of MAPKs. Oncogene , 3100 - 3112
    44. 44)
      • K. Radhakrishnan . Comparison of numerical techniques for integration of stiff ordinary differential equations arising in combustion.
    45. 45)
      • K. Radhakrishnan . LSENS: multipurpose kinetics and sensitivity analysis code. AIAA J. , 848 - 855
    46. 46)
      • B.B. Friday , A.A. Adjei . Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated protein kinase cascade with MEK inhibitors for cancer therapy. Clin. Cancer Res. , 342 - 346
http://iet.metastore.ingenta.com/content/journals/10.1049/iet-syb.2009.0010
Loading

Related content

content/journals/10.1049/iet-syb.2009.0010
pub_keyword,iet_inspecKeyword,pub_concept
6
6
Loading
Print this page
This is a required field
Please enter a valid email address