Good MC, Zalatan JG, Lim WA. Scaffold proteins: hubs for controlling the flow of cellular information. Science. 2011;332:680–6.
Langeberg LK, Scott JD. Signalling scaffolds and local organization of cellular behaviour. Nat Rev Mol Cell Biol. 2015;16:232–44.
Morrison DK. KSR: a MAPK scaffold of the Ras pathway? J Cell Sci. 2001;114:1609–12.
Yasuda J, Whitmarsh AJ, Cavanagh J, Sharma M, Davis RJ. The JIP group of mitogen-activated protein kinase scaffold proteins. Mol Cell Biol. 1999;19:7245–54.
Roy M, Li Z, Sacks DB. IQGAP1 is a scaffold for mitogen-activated protein kinase signaling. Mol Cell Biol. 2005;25:7940–52.
McDonald PH, Chow CW, Miller WE, Laporte SA, Field ME, Lin FT, et al. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science. 2000;290:1574–7.
Garai A, Zeke A, Gogl G, Toro I, Fordos F, Blankenburg H, et al. Specificity of linear motifs that bind to a common mitogen-activated protein kinase docking groove. Sci Signal. 2012;5:ra74.
Roskoski Jr R. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res. 2012;66:105–43.
Whisenant TC, Ho DT, Benz RW, Rogers JS, Kaake RM, Gordon EA, et al. Computational prediction and experimental verification of new MAP kinase docking sites and substrates including Gli transcription factors. PLoS Comput Biol. 2010;6:e1000908.
Tanoue T, Adachi M, Moriguchi T, Nishida E. A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat Cell Biol. 2000;2:110–6.
Lee T, Hoofnagle AN, Kabuyama Y, Stroud J, Min X, Goldsmith EJ, et al. Docking motif interactions in MAP kinases revealed by hydrogen exchange mass spectrometry. Mol Cell. 2004;14:43–55.
Jacobs D, Glossip D, Xing H, Muslin AJ, Kornfeld K. Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev. 1999;13:163–75.
Sheridan DL, Kong Y, Parker SA, Dalby KN, Turk BE. Substrate discrimination among mitogen-activated protein kinases through distinct docking sequence motifs. J Biol Chem. 2008;283:19511–20.
Jacobs D, Beitel GJ, Clark SG, Horvitz HR, Kornfeld K. Gain-of-function mutations in the Caenorhabditis elegans lin-1 ETS gene identify a C-terminal regulatory domain phosphorylated by ERK MAP kinase. Genetics. 1998;149:1809–22.
Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J. Molecular interpretation of ERK signal duration by immediate early gene products. Nat Cell Biol. 2002;4:556–64.
Kosako H, Yamaguchi N, Aranami C, Ushiyama M, Kose S, Imamoto N, et al. Phosphoproteomics reveals new ERK MAP kinase targets and links ERK to nucleoporin-mediated nuclear transport. Nat Struct Mol Biol. 2009;16:1026–35.
Matsubayashi Y, Fukuda M, Nishida E. Evidence for existence of a nuclear pore complex-mediated, cytosol-independent pathway of nuclear translocation of ERK MAP kinase in permeabilized cells. J Biol Chem. 2001;276:41755–60.
Mace PD, Wallez Y, Egger MF, Dobaczewska MK, Robinson H, Pasquale EB, et al. Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK. Nat Commun. 2013;4:1681.
Pedersen SF. The Na+/H+ exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death. Pflugers Arch. 2006;452:249–59.
Boedtkjer E, Bunch L, Pedersen SF. Physiology, pharmacology and pathophysiology of the pH regulatory transport proteins NHE1 and NBCn1: similarities, differences, and implications for cancer therapy. Curr Pharm Des. 2012;18:1345–71.
Ganz MB, Pachter JA, Barber DL. Multiple receptors coupled to adenylate cyclase regulate Na-H exchange independent of cAMP. J Biol Chem. 1990;265:8989–92.
Lauritzen G, Stock CM, Lemaire J, Lund SF, Jensen MF, Damsgaard B, et al. The Na+/H+ exchanger NHE1, but not the Na+, HCO3-cotransporter NBCn1, regulates motility of MCF7 breast cancer cells expressing constitutively active ErbB2. Cancer Lett. 2012;317:172–83.
Wakabayashi S, Bertrand B, Shigekawa M, Fafournoux P, Pouyssegur J. Growth factor activation and “H+-sensing” of the Na+/H+ exchanger isoform 1 (NHE1). Evidence for an additional mechanism not requiring direct phosphorylation. J Biol Chem. 1994;269:5583–8.
Haworth RS, McCann C, Snabaitis AK, Roberts NA, Avkiran M. Stimulation of the plasma membrane Na+/H+ exchanger NHE1 by sustained intracellular acidosis. Evidence for a novel mechanism mediated by the ERK pathway. J Biol Chem. 2003;278:31676–84.
Malo ME, Li L, Fliegel L. Mitogen-activated protein kinase-dependent activation of the Na+/H+ exchanger is mediated through phosphorylation of amino acids Ser770 and Ser771. J Biol Chem. 2007;282:6292–9.
Pedersen SF, Darborg BV, Rasmussen M, Nylandsted J, Hoffmann EK. The Na+/H+ exchanger, NHE1, differentially regulates mitogen-activated protein kinase subfamilies after osmotic shrinkage in Ehrlich Lettre Ascites cells. Cell Physiol Biochem. 2007;20:735–50.
Takahashi E, Abe J, Gallis B, Aebersold R, Spring DJ, Krebs EG, et al. p90(RSK) is a serum-stimulated Na+/H+ exchanger isoform-1 kinase. Regulatory phosphorylation of serine 703 of Na+/H+ exchanger isoform-1. J Biol Chem. 1999;274:20206–14.
Pedersen SF, Darborg BV, Rentsch ML, Rasmussen M. Regulation of mitogen-activated protein kinase pathways by the plasma membrane Na+/H+ exchanger, NHE1. Arch Biochem Biophys. 2007;462:195–201.
Liu H, Stupak J, Zheng J, Keller BO, Brix BJ, Fliegel L, et al. Open tubular immobilized metal ion affinity chromatography combined with MALDI MS and MS/MS for identification of protein phosphorylation sites. Anal Chem. 2004;76:4223–32.
Javadov S, Baetz D, Rajapurohitam V, Zeidan A, Kirshenbaum LA, Karmazyn M. Antihypertrophic effect of Na+/H+ exchanger isoform 1 inhibition is mediated by reduced mitogen-activated protein kinase activation secondary to improved mitochondrial integrity and decreased generation of mitochondrial-derived reactive oxygen species. J Pharmacol Exp Ther. 2006;317:1036–43.
Mukhin YV, Garnovskaya MN, Ullian ME, Raymond JR. ERK is regulated by sodium-proton exchanger in rat aortic vascular smooth muscle cells. J Biol Chem. 2004;279:1845–52.
Rentsch ML, Ossum CG, Hoffmann EK, Pedersen SF. Roles of Na+/H+ exchange in regulation of p38 mitogen-activated protein kinase activity and cell death after chemical anoxia in NIH3T3 fibroblasts. Pflugers Arch. 2007;454:649–62.
Bandyopadhyay S, Chiang CY, Srivastava J, Gersten M, White S, Bell R, et al. A human MAP kinase interactome. Nat Methods. 2010;7:801–5.
Karki P, Li X, Schrama D, Fliegel L. B-Raf associates with and activates the NHE1 isoform of the Na+/H+ exchanger. J Biol Chem. 2011;286:13096–105.
Norholm AB, Hendus-Altenburger R, Bjerre G, Kjaergaard M, Pedersen SF, Kragelund BB. The intracellular distal tail of the Na+/H+ exchanger NHE1 is intrinsically disordered: implications for NHE1 trafficking. Biochemistry. 2011;50:3469–80.
Hendus-Altenburger R, Kragelund BB, Pedersen SF. Structural dynamics and regulation of the mammalian SLC9A family of Na+/H+ exchangers. Curr Top Membr. 2014;73:69–148.
Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT. Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol. 2004;337:635–45.
Iakoucheva LM, Brown CJ, Lawson JD, Obradovic Z, Dunker AK. Intrinsic disorder in cell-signaling and cancer-associated proteins. J Mol Biol. 2002;323:573–84.
Cortese MS, Uversky VN, Keith DA. Intrinsic disorder in scaffold proteins: getting more from less. Prog Biophys Mol Biol. 2008;98:85–106.
Kragelj J, Palencia A, Nanao MH, Maurin D, Bouvignies G, Blackledge M, et al. Structure and dynamics of the MKK7-JNK signaling complex. Proc Natl Acad Sci U S A. 2015;112:3409–14.
Rotin D, Grinstein S. Impaired cell volume regulation in Na(+)-H+ exchange-deficient mutants. Am J Physiol. 1989;257:C1158–65.
Lloyd AC. Distinct functions for ERKs? J Biol. 2006;5:13.
Robbins DJ, Zhen E, Owaki H, Vanderbilt CA, Ebert D, Geppert TD, et al. Regulation and properties of extracellular signal-regulated protein kinases 1 and 2 in vitro. J Biol Chem. 1993;268:5097–106.
Zhou B, Zhang ZY. The activity of the extracellular signal-regulated kinase 2 is regulated by differential phosphorylation in the activation loop. J Biol Chem. 2002;277:13889–99.
Yang SH, Whitmarsh AJ, Davis RJ, Sharrocks AD. Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1. EMBO J. 1998;17:1740–9.
Marty MT, Baldwin AJ, Marklund EG, Hochberg GK, Benesch JL, Robinson CV. Bayesian deconvolution of mass and ion mobility spectra: from binary interactions to polydisperse ensembles. Anal Chem. 2015;87:4370–6.
Kaoud TS, Devkota AK, Harris R, Rana MS, Abramczyk O, Warthaka M, et al. Activated ERK2 is a monomer in vitro with or without divalent cations and when complexed to the cytoplasmic scaffold PEA-15. Biochemistry. 2011;50:4568–78.
Lundby A, Secher A, Lage K, Nordsborg NB, Dmytriyev A, Lundby C, et al. Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues. Nat Commun. 2012;3:876.
Theillet FX, Smet-Nocca C, Liokatis S, Thongwichian R, Kosten J, Yoon MK, et al. Cell signaling, post-translational protein modifications and NMR spectroscopy. J Biomol NMR. 2012;54:217–36.
Smet-Nocca C, Launay H, Wieruszeski JM, Lippens G, Landrieu I. Unraveling a phosphorylation event in a folded protein by NMR spectroscopy: phosphorylation of the Pin1 WW domain by PKA. J Biomol NMR. 2013;55:323–37.
Lagana A, Vadnais J, Le PU, Nguyen TN, Laprade R, Nabi IR, et al. Regulation of the formation of tumor cell pseudopodia by the Na+/H+ exchanger NHE1. J Cell Sci. 2000;113(Pt 20):3649–62.
Schneider L, Stock CM, Dieterich P, Jensen BH, Pedersen LB, Satir P, et al. The Na+/H+ exchanger NHE1 is required for directional migration stimulated via PDGFR-alpha in the primary cilium. J Cell Biol. 2009;185:163–76.
Martin C, Pedersen SF, Schwab A, Stock C. Intracellular pH gradients in migrating cells. Am J Physiol Cell Physiol. 2011;300:C490–5.
Pedraz-Cuesta E, Fredsted J, Jensen HH, Bornebusch A, Nejsum LN, Kragelund BB, et al. Prolactin signaling stimulates invasion via the Na+/H+ exchanger NHE1 in T47D human breast cancer cells. Mol Endocrinol. 2015; in revision
Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, et al. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell. 2006;127:635–48.
Uversky VN. Multitude of binding modes attainable by intrinsically disordered proteins: a portrait gallery of disorder-based complexes. Chem Soc Rev. 2011;40:1623–34.
Bhattacharyya RP, Remenyi A, Good MC, Bashor CJ, Falick AM, Lim WA. The Ste5 scaffold allosterically modulates signaling output of the yeast mating pathway. Science. 2006;311:822–6.
Wang Y, Fisher JC, Mathew R, Ou L, Otieno S, Sublet J, et al. Intrinsic disorder mediates the diverse regulatory functions of the Cdk inhibitor p21. Nat Chem Biol. 2011;7:214–21.
Mittag T, Marsh J, Grishaev A, Orlicky S, Lin H, Sicheri F, et al. Structure/function implications in a dynamic complex of the intrinsically disordered Sic1 with the Cdc4 subunit of an SCF ubiquitin ligase. Structure. 2010;18:494–506.
Tang X, Orlicky S, Mittag T, Csizmok V, Pawson T, Forman-Kay JD, et al. Composite low affinity interactions dictate recognition of the cyclin-dependent kinase inhibitor Sic1 by the SCFCdc4 ubiquitin ligase. Proc Natl Acad Sci U S A. 2012;109:3287–92.
Perham RN. Self-assembly of biological macromolecules. Philos Trans R Soc Lond B Biol Sci. 1975;272:123–36.
Bardwell AJ, Abdollahi M, Bardwell L. Docking sites on mitogen-activated protein kinase (MAPK) kinases, MAPK phosphatases and the Elk-1 transcription factor compete for MAPK binding and are crucial for enzymic activity. Biochem J. 2003;370:1077–85.
Hisamitsu T, Ammar YB, Nakamura TY, Wakabayashi S. Dimerization is crucial for the function of the Na+/H+ exchanger NHE1. Biochemistry. 2006;45:13346–55.
Balasu MC, Spiridon LN, Miron S, Craescu CT, Scheidig AJ, Petrescu AJ, et al. Interface analysis of the complex between ERK2 and PTP-SL. PLoS One. 2009;4:e5432.
Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, et al. A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008;105:10762–7.
Khaled AR, Moor AN, Li A, Kim K, Ferris DK, Muegge K, et al. Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization. Mol Cell Biol. 2001;21:7545–57.
Grenier AL, Abu-Ihweij K, Zhang G, Ruppert SM, Boohaker R, Slepkov ER, et al. Apoptosis-induced alkalinization by the Na+/H+ exchanger isoform 1 is mediated through phosphorylation of amino acids Ser726 and Ser729. Am J Physiol Cell Physiol. 2008;295:C883–96.
Odunewu A, Fliegel L. Acidosis-mediated regulation of the NHE1 isoform of the Na+/H+ exchanger in renal cells. Am J Physiol Renal Physiol. 2013;305:F370–81.
Rigor RR, Damoc C, Phinney BS, Cala PM. Phosphorylation and activation of the plasma membrane Na+/H+ exchanger (NHE1) during osmotic cell shrinkage. PLoS One. 2011;6:e29210.
Selenko P, Frueh DP, Elsaesser SJ, Haas W, Gygi SP, Wagner G. In situ observation of protein phosphorylation by high-resolution NMR spectroscopy. Nat Struct Mol Biol. 2008;15:321–9.
Kjaergaard M, Norholm AB, Hendus-Altenburger R, Pedersen SF, Poulsen FM, Kragelund BB. Temperature-dependent structural changes in intrinsically disordered proteins: formation of alpha-helices or loss of polyproline II? Protein Sci. 2010;19:1555–64.
Obenauer JC, Cantley LC, Yaffe MB. Scansite 2.0: proteome-wide prediction of cell signaling interactions using short sequence motifs. Nucleic Acids Res. 2003;31:3635–41.
Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011;7:539.
Xue B, Dunbrack RL, Williams RW, Dunker AK, Uversky VN. PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta. 2010;1804:996–1010.
Ward JJ, McGuffin LJ, Bryson K, Buxton BF, Jones DT. The DISOPRED server for the prediction of protein disorder. Bioinformatics. 2004;20:2138–9.
Delaglio F, Grzesiek S, Vuister GW, Zhu G, Pfeifer J, Bax A. NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J Biomol NMR. 1995;6:277–93.
Vranken WF, Boucher W, Stevens TJ, Fogh RH, Pajon A, Llinas M, et al. The CCPN data model for NMR spectroscopy: development of a software pipeline. Proteins. 2005;59:687–96.
Sobott F, Hernandez H, McCammon MG, Tito MA, Robinson CV. A tandem mass spectrometer for improved transmission and analysis of large macromolecular assemblies. Anal Chem. 2002;74:1402–7.
Hernandez H, Robinson CV. Determining the stoichiometry and interactions of macromolecular assemblies from mass spectrometry. Nat Protoc. 2007;2:715–26.
Gogl G, Toro I, Remenyi A. Protein-peptide complex crystallization: a case study on the ERK2 mitogen-activated protein kinase. Acta Crystallogr D Biol Crystallogr. 2013;69:486–9.
Fiser A, Sali A. Modeller: generation and refinement of homology-based protein structure models. Methods Enzymol. 2003;374:461–91.
Pedersen SF, King SA, Nygaard EB, Rigor RR, Cala PM. NHE1 inhibition by amiloride- and benzoylguanidine-type compounds. Inhibitor binding loci deduced from chimeras of NHE1 homologues with endogenous differences in inhibitor sensitivity. J Biol Chem. 2007;282:19716–27.