Cell regulation: determined to signal discrete cooperation.

Do kinases cascade? How well is cell regulation understood? What are the best ways to model regulatory systems? Attempts to answer such questions can have bearings on the way in which research is conducted. Fortunately there are recurring themes in regulatory processes from many different cellular contexts, which might provide useful guidance. Three principles seem to be almost universal: regulatory interactions are cooperative; regulatory decisions are made by large dynamic protein complexes; and regulation is intricately networked. A fourth principle, although not universal, is remarkably common: regulatory proteins are actively placed where they are needed. Here, I argue that the true nature of cell signalling and our perceptions of it are in a state of discord. This raises the question: Are our misconceptions detrimental to progress in biomedical science?

[1]  M. Spector,et al.  Warburg effect revisited: merger of biochemistry and molecular biology. , 1981, Science.

[2]  S. Cevik,et al.  Intraflagellar transport: from molecular characterisation to mechanism. , 2008, Frontiers in bioscience : a journal and virtual library.

[3]  D. Owen Linking endocytic cargo to clathrin: structural and functional insights into coated vesicle formation. , 2004, Biochemical Society transactions.

[4]  T. Pawson,et al.  Signaling through scaffold, anchoring, and adaptor proteins. , 1997, Science.

[5]  S. Mili,et al.  Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions , 2008, Nature.

[6]  Malgorzata Schelder,et al.  Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila. , 2006, Molecular cell.

[7]  E. Krebs,et al.  The MAPK signaling cascade , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  U. Hoffmann‐Rohrer,et al.  Nuclear myosin I acts in concert with polymeric actin to drive RNA polymerase I transcription. , 2008, Genes & development.

[9]  J. Tavaré,et al.  Identifying protein kinase substrates: hunting for the organ-grinder's monkeys. , 2004, Trends in biochemical sciences.

[10]  G. Drewes,et al.  MAPs, MARKs and microtubule dynamics. , 1998, Trends in biochemical sciences.

[11]  R. Heald,et al.  Genome-wide analysis demonstrates conserved localization of messenger RNAs to mitotic microtubules , 2007, The Journal of cell biology.

[12]  D. Hyde,et al.  Gα Proteins in Drosophila: Structure and Developmental Expression , 1993 .

[13]  J. Hesketh,et al.  Targeting of transcripts encoding membrane proteins in polarized epithelia: RNA-protein binding studies of the SGLT1 3'-UTR. , 2008, Biochemical Society transactions.

[14]  D. Cooper,et al.  Layers of organization of cAMP microdomains in a simple cell. , 2006, Biochemical Society transactions.

[15]  P. Bork,et al.  Systematic Discovery of In Vivo Phosphorylation Networks , 2007, Cell.

[16]  Angus I. Lamond,et al.  Nuclear functions in space and time: Gene expression in a dynamic, constrained environment , 2008, FEBS letters.

[17]  B. Schnapp,et al.  Trafficking of signaling modules by kinesin motors , 2003, Journal of Cell Science.

[18]  D. Barford,et al.  Lining the pockets of kinases and phosphatases. , 2006, Current opinion in structural biology.

[19]  Aron W Fenton,et al.  Allostery: an illustrated definition for the 'second secret of life'. , 2008, Trends in biochemical sciences.

[20]  G. Johnson,et al.  Tau phosphorylation: physiological and pathological consequences. , 2005, Biochimica et biophysica acta.

[21]  P. Bork,et al.  Linear Motif Atlas for Phosphorylation-Dependent Signaling , 2008, Science Signaling.

[22]  R. Foisner,et al.  Nucleoplasmic lamins and their interaction partners, LAP2α, Rb, and BAF, in transcriptional regulation , 2007, The FEBS journal.

[23]  M. Nakao,et al.  In situ SUMOylation analysis reveals a modulatory role of RanBP2 in the nuclear rim and PML bodies. , 2006, Experimental cell research.

[24]  Akihiko Konagaya,et al.  Compensation effect of the MAPK cascade on formation of phospho-protein gradients. , 2006, Bio Systems.

[25]  Rosa Bernardi,et al.  Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies , 2007, Nature Reviews Molecular Cell Biology.

[26]  Carsten Schultz,et al.  Live-Cell Imaging of Enzyme-Substrate Interaction Reveals Spatial Regulation of PTP1B , 2007, Science.

[27]  H. Krause,et al.  Apical Localization of wingless Transcripts Is Required for Wingless Signaling , 2001, Cell.

[28]  E. O’Shea,et al.  Global analysis of protein expression in yeast , 2003, Nature.

[29]  Corinne J. Smith,et al.  Natively unfolded domains in endocytosis: hooks, lines and linkers , 2004, EMBO reports.

[30]  J. Pascual,et al.  Canonical and Alternative MAPK Signaling , 2007, Cell cycle.

[31]  Sonia Longhi,et al.  Assessing protein disorder and induced folding , 2005, Proteins.

[32]  N. H. Uhlenhaut,et al.  Transcriptional regulators in kidney disease: gatekeepers of renal homeostasis. , 2008, Trends in genetics : TIG.

[33]  J. Scholey Intraflagellar transport motors in cilia: moving along the cell's antenna , 2008, The Journal of cell biology.

[34]  J. Lehár,et al.  High-order combination effects and biological robustness , 2008, Molecular systems biology.

[35]  J. Graham,et al.  Architecture and function , 1993 .

[36]  B. C. Carter,et al.  Multiple-motor based transport and its regulation by Tau , 2007, Proceedings of the National Academy of Sciences.

[37]  Florence Besse,et al.  Translational control of localized mRNAs: restricting protein synthesis in space and time , 2008, Nature Reviews Molecular Cell Biology.

[38]  S. Gross Hither and yon: a review of bi-directional microtubule-based transport , 2004, Physical biology.

[39]  István Simon,et al.  BIOINFORMATICS ORIGINAL PAPER doi:10.1093/bioinformatics/btm035 Structural bioinformatics Local structural disorder imparts plasticity on linear motifs , 2022 .

[40]  T. Gibson,et al.  A careful disorderliness in the proteome: Sites for interaction and targets for future therapies , 2008, FEBS letters.

[41]  Richard J. Edwards,et al.  Masking residues using context-specific evolutionary conservation significantly improves short linear motif discovery , 2009, Bioinform..

[42]  Georgi Georgiev,et al.  Reaction-Diffusion Modeling ERK- and STAT-Interaction Dynamics , 2006, EURASIP J. Bioinform. Syst. Biol..

[43]  Qihong Zhang,et al.  Gli2 and Gli3 Localize to Cilia and Require the Intraflagellar Transport Protein Polaris for Processing and Function , 2005, PLoS genetics.

[44]  K. N. Bradley,et al.  Ca2+ microdomains in smooth muscle. , 2006, Cell calcium.

[45]  Michael Knop,et al.  Spatial regulation of Fus3 MAP kinase activity through a reaction-diffusion mechanism in yeast pheromone signalling , 2007, Nature Cell Biology.

[46]  R. Lehmann,et al.  oskar organizes the germ plasm and directs localization of the posterior determinant nanos , 1991, Cell.

[47]  Marc S. Cortese,et al.  Flexible nets , 2005, The FEBS journal.

[48]  Kohei Miyazono,et al.  TGF-β signalling from cell membrane to nucleus through SMAD proteins , 1997, Nature.

[49]  J. Blenis,et al.  ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions , 2004, Microbiology and Molecular Biology Reviews.

[50]  C. Sawyers,et al.  The phosphatidylinositol 3-Kinase–AKT pathway in human cancer , 2002, Nature Reviews Cancer.

[51]  Jay Vyas,et al.  Viral infection and human disease--insights from minimotifs. , 2008, Frontiers in bioscience : a journal and virtual library.

[52]  M. Welte,et al.  Bidirectional Transport along Microtubules , 2004, Current Biology.

[53]  Alex Braiman,et al.  Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1 , 2006, Nature Structural &Molecular Biology.

[54]  The cell biological basis of ciliary disease , 2008 .

[55]  Eduardo Sontag,et al.  A passivity-based stability criterion for a class of biochemical reaction networks. , 2008, Mathematical biosciences and engineering : MBE.

[56]  M. Pagano,et al.  Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. , 2005, Molecular cell.

[57]  D. Seelow,et al.  Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis , 2007, Nature Genetics.

[58]  M. Rosenfeld,et al.  Ligand-specific allosteric regulation of coactivator functions of androgen receptor in prostate cancer cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Lila M. Gierasch,et al.  Sending Signals Dynamically , 2009, Science.

[60]  J. Elf,et al.  Spontaneous separation of bi-stable biochemical systems into spatial domains of opposite phases. , 2004, Systems biology.

[61]  Christian von Mering,et al.  STRING 8—a global view on proteins and their functional interactions in 630 organisms , 2008, Nucleic Acids Res..

[62]  S. Bhattacharya,et al.  Signaling through the JAK/STAT pathway, recent advances and future challenges. , 2002, Gene.

[63]  Ram Dixit,et al.  Differential Regulation of Dynein and Kinesin Motor Proteins by Tau , 2008, Science.

[64]  J. Gall,et al.  Subnuclear organelles: new insights into form and function. , 2006, Trends in cell biology.

[65]  Adrian Whitty,et al.  Cooperativity and biological complexity. , 2008, Nature chemical biology.

[66]  Lan V. Zhang,et al.  Evidence for dynamically organized modularity in the yeast protein–protein interaction network , 2004, Nature.

[67]  J. Ross,et al.  Cargo transport: molecular motors navigate a complex cytoskeleton. , 2008, Current opinion in cell biology.

[68]  R. Nusse,et al.  Wnt signaling: a common theme in animal development. , 1997, Genes & development.

[69]  J. Condeelis,et al.  Spatial regulation of β-actin translation by Src-dependent phosphorylation of ZBP1 , 2005, Nature.

[70]  P. Tomançak,et al.  Global Analysis of mRNA Localization Reveals a Prominent Role in Organizing Cellular Architecture and Function , 2007, Cell.

[71]  F. Hildebrandt,et al.  Nephronophthisis-associated ciliopathies. , 2007, Journal of the American Society of Nephrology : JASN.

[72]  E. Racker Warburg effect revisited. , 1981, Science.

[73]  K. Chiam,et al.  Oscillations in intracellular signaling cascades. , 2007, Physical review. E, Statistical, nonlinear, and soft matter physics.

[74]  Anna Akhmanova,et al.  Tracking the ends: a dynamic protein network controls the fate of microtubule tips , 2008, Nature Reviews Molecular Cell Biology.

[75]  G. Superti-Furga,et al.  Structural Coupling of SH2-Kinase Domains Links Fes and Abl Substrate Recognition and Kinase Activation , 2008, Cell.

[76]  Niall J. Haslam,et al.  Understanding eukaryotic linear motifs and their role in cell signaling and regulation. , 2008, Frontiers in bioscience : a journal and virtual library.

[77]  Nobutaka Hirokawa,et al.  Molecular motors and mechanisms of directional transport in neurons , 2005, Nature Reviews Neuroscience.

[78]  E. Mandelkow,et al.  On the structure of microtubules, tau, and paired helical filaments , 1995, Neurobiology of Aging.

[79]  G. Superti-Furga,et al.  A crystal milestone: the structure of regulated Src. , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[80]  N. Hannett,et al.  Activated Signal Transduction Kinases Frequently Occupy Target Genes , 2006, Science.

[81]  Steven D. Gribble,et al.  Robustness in complex systems , 2001, Proceedings Eighth Workshop on Hot Topics in Operating Systems.

[82]  Boguslaw Stec,et al.  The Fas/FADD death domain complex structure unravels signaling by receptor clustering , 2008, Nature.

[83]  A. Dunker,et al.  Disorder and sequence repeats in hub proteins and their implications for network evolution. , 2006, Journal of proteome research.

[84]  G. Bossi,et al.  Ser58 of mouse p53 is the homologue of human Ser46 and is phosphorylated by HIPK2 in apoptosis , 2006, Cell Death and Differentiation.

[85]  N. Hirokawa mRNA Transport in Dendrites: RNA Granules, Motors, and Tracks , 2006, The Journal of Neuroscience.

[86]  H. Stenmark,et al.  Protein sorting into multivesicular endosomes. , 2003, Current opinion in cell biology.

[87]  M. Adams,et al.  Recent advances in the molecular pathology, cell biology and genetics of ciliopathies , 2008, Journal of Medical Genetics.

[88]  N. Dillon The impact of gene location in the nucleus on transcriptional regulation. , 2008, Developmental cell.

[89]  M J May,et al.  NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. , 1998, Annual review of immunology.

[90]  Christine A. Orengo,et al.  Inferring Function Using Patterns of Native Disorder in Proteins , 2007, PLoS Comput. Biol..

[91]  S. Gasser,et al.  The nuclear envelope and transcriptional control , 2007, Nature Reviews Genetics.

[92]  M. Fornerod,et al.  The inner nuclear envelope as a transcription factor resting place , 2007, EMBO reports.

[93]  A. Nebenführ,et al.  The Tail that Wags the Dog: The Globular Tail Domain Defines the Function of Myosin V/XI , 2008, Traffic.

[94]  S. Itzkovitz,et al.  Functional atlas of the integrin adhesome , 2007, Nature Cell Biology.

[95]  A. Heuck,et al.  Directional mRNA transport in eukaryotes: lessons from yeast , 2006, Cellular and Molecular Life Sciences.

[96]  H. Dyson,et al.  Intrinsically unstructured proteins and their functions , 2005, Nature Reviews Molecular Cell Biology.

[97]  C. Turner,et al.  Paxillin comes of age , 2008, Journal of Cell Science.

[98]  Arjun Guha,et al.  Understanding morphogen gradients: a problem of dispersion and containment. , 2007, Current opinion in genetics & development.

[99]  Heinrich Sticht,et al.  A computational strategy for the prediction of functional linear peptide motifs in proteins , 2007, Bioinform..

[100]  L. Bardwell,et al.  Mechanisms of MAPK signalling specificity. , 2006, Biochemical Society transactions.

[101]  P. Gilligan,et al.  Reining in RNA , 2008, EMBO reports.

[102]  Anna Akhmanova,et al.  Capturing protein tails by CAP-Gly domains. , 2008, Trends in biochemical sciences.

[103]  S. Gross,et al.  Cargo Transport: Two Motors Are Sometimes Better Than One , 2007, Current Biology.

[104]  A. Giuditta,et al.  Axonal and presynaptic protein synthesis: new insights into the biology of the neuron , 2002, Trends in Neurosciences.

[105]  István Simon,et al.  Prediction of protein disorder at the domain level. , 2007, Current protein & peptide science.

[106]  S. R. Wicks,et al.  Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. , 2004, Genes & development.

[107]  D. Morrison,et al.  Regulation of MAP kinase signaling modules by scaffold proteins in mammals. , 2003, Annual review of cell and developmental biology.

[108]  Grant W. Brown,et al.  Functional Targeting of DNA Damage to a Nuclear Pore-Associated SUMO-Dependent Ubiquitin Ligase , 2008, Science.

[109]  C. Malbon Developmental cell biology: G proteins in development , 2005, Nature Reviews Molecular Cell Biology.

[110]  Allegra Via,et al.  Phospho.ELM: a database of phosphorylation sites—update 2008 , 2007, Nucleic Acids Res..

[111]  V. Rybin,et al.  Decoding of Methylated Histone H3 Tail by the Pygo-BCL9 Wnt Signaling Complex , 2008, Molecular cell.

[112]  D. Tollervey,et al.  An Endoribonuclease Functionally Linked to Perinuclear mRNP Quality Control Associates with the Nuclear Pore Complexes , 2009, PLoS biology.

[113]  Olivier Poch,et al.  A new protein linear motif benchmark for multiple sequence alignment software , 2008, BMC Bioinformatics.

[114]  H. Herrmann,et al.  The nuclear lamina , 2007, The FEBS journal.

[115]  R. Goodman,et al.  CBP/p300 in cell growth, transformation, and development. , 2000, Genes & development.

[116]  Leszek Rychlewski,et al.  ELM server: a new resource for investigating short functional sites in modular eukaryotic proteins , 2003, Nucleic Acids Res..

[117]  C. Nüsslein-Volhard,et al.  A gradient of bicoid protein in Drosophila embryos , 1988, Cell.

[118]  Jörg Stelling,et al.  Signaling cascades as cellular devices for spatial computations , 2009, Journal of mathematical biology.

[119]  Nicholas Katsanis,et al.  The ciliopathies: an emerging class of human genetic disorders. , 2006, Annual review of genomics and human genetics.