Endocytosis and signalling: A meeting with mathematics

Although endocytosis has traditionally been understood as a signal attenuation mechanism, an emerging view considers endocytosis as an integral part of signal propagation and processing. On the short time scale, trafficking of endocytic vesicles contributes to signal propagation from the surface to distant targets, with bi‐directional communication between signalling and trafficking. Mathematical modelling helps combine the mechanistic, molecular knowledge with rigorous analysis of the complex output dynamics of endocytosis in time and space. Simulations reveal novel roles for endocytosis, including the control of cell polarity, enhancing the spatial signal propagation, and controlling the signal magnitudes, kinetics, and synchronization with stimulus dynamics.

[1]  M. Gonzalez-Gaitan,et al.  Endocytosis, asymmetric cell division, stem cells and cancer: Unus pro omnibus, omnes pro uno , 2009, Molecular oncology.

[2]  L. E. Johannessen,et al.  The inhibitory effect of ErbB2 on epidermal growth factor-induced formation of clathrin-coated pits correlates with retention of epidermal growth factor receptor-ErbB2 oligomeric complexes at the plasma membrane. , 2005, Molecular biology of the cell.

[3]  Mark von Zastrow,et al.  Signal transduction and endocytosis: close encounters of many kinds , 2002, Nature Reviews Molecular Cell Biology.

[4]  Gáspár Jékely,et al.  Regulators of endocytosis maintain localized receptor tyrosine kinase signaling in guided migration. , 2005, Developmental cell.

[5]  Eric Karsenti,et al.  Stathmin-Tubulin Interaction Gradients in Motile and Mitotic Cells , 2004, Science.

[6]  H. Steven Wiley,et al.  Quantitative Analysis of HER 2-mediated Effects on HER 2 and Epidermal Growth Factor Receptor Endocytosis DISTRIBUTION OF HOMO-AND HETERODIMERS DEPENDS ON RELATIVE HER 2 LEVELS * , 2003 .

[7]  William C Mobley,et al.  Signaling endosome hypothesis: A cellular mechanism for long distance communication. , 2004, Journal of neurobiology.

[8]  C DeLisi,et al.  Receptor-mediated endocytosis: a model and its implications for experimental analysis. , 1984, The American journal of physiology.

[9]  B. Kholodenko,et al.  Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor* , 1999, The Journal of Biological Chemistry.

[10]  Boris N. Kholodenko,et al.  Untangling the signalling wires , 2007, Nature Cell Biology.

[11]  R. Campenot,et al.  Retrograde Support of Neuronal Survival Without Retrograde Transport of Nerve Growth Factor , 2002, Science.

[12]  Roland Eils,et al.  An ultrasensitive sorting mechanism for EGF Receptor Endocytosis , 2008, BMC Systems Biology.

[13]  D. Stolz,et al.  Characterization of Endocytic Vesicles Using Magnetic Microbeads Coated with Signalling Ligands , 2005, Traffic.

[14]  Ira Mellman,et al.  The Receptor Recycling Pathway Contains Two Distinct Populations of Early Endosomes with Different Sorting Functions , 1999, The Journal of cell biology.

[15]  B. Kholodenko,et al.  Ligand-dependent responses of the ErbB signaling network: experimental and modeling analyses , 2007, Molecular systems biology.

[16]  Jason M Haugh,et al.  Localization of receptor-mediated signal transduction pathways: the inside story. , 2002, Molecular interventions.

[17]  P. Lipsky,et al.  Sterol-independent, sterol response element-dependent, regulation of low density lipoprotein receptor gene expression. , 1998, Journal of lipid research.

[18]  Y. Kalaidzidis,et al.  Rab Conversion as a Mechanism of Progression from Early to Late Endosomes , 2005, Cell.

[19]  P. Swaan,et al.  Endocytic mechanisms for targeted drug delivery. , 2007, Advanced drug delivery reviews.

[20]  D. Lauffenburger,et al.  Internalized Epidermal Growth Factor Receptors Participate in the Activation of p21 ras in Fibroblasts* , 1999, The Journal of Biological Chemistry.

[21]  L. Lo Leggio,et al.  Insulin-stimulated GLUT4 glucose transporter recycling. A problem in membrane protein subcellular trafficking through multiple pools. , 1994, The Journal of biological chemistry.

[22]  Jens Timmer,et al.  Systems-level interactions between insulin–EGF networks amplify mitogenic signaling , 2009, Molecular systems biology.

[23]  Boris N Kholodenko,et al.  Four‐dimensional dynamics of MAPK information‐processing systems , 2009, Wiley interdisciplinary reviews. Systems biology and medicine.

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

[25]  S. Polo,et al.  Endocytosis Conducts the Cell Signaling Orchestra , 2006, Cell.

[26]  M L Shuler,et al.  A mathematical model of the trafficking of acid-dependent enveloped viruses: application to the binding, uptake, and nuclear accumulation of baculovirus. , 1997, Biotechnology and bioengineering.

[27]  Alexandre Benmerah,et al.  Clathrin‐Coated Pits: Vive La Différence? , 2007, Traffic.

[28]  F H Ruddle,et al.  Transcriptional regulation by iron of the gene for the transferrin receptor , 1986, Molecular and cellular biology.

[29]  Karsten Weis,et al.  Visualization of a Ran-GTP Gradient in Interphase and Mitotic Xenopus Egg Extracts , 2002, Science.

[30]  G. Holzwarth,et al.  Fast vesicle transport in PC12 neurites: velocities and forces , 2004, European Biophysics Journal.

[31]  F. W. Wiegel,et al.  The distribution of cell surface proteins on spreading cells. Comparison of theory with experiment. , 1988, Biophysical journal.

[32]  R. Campenot,et al.  Retrograde transport of neurotrophins: fact and function. , 2004, Journal of neurobiology.

[33]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[34]  Eran Perlson,et al.  Vimentin-Dependent Spatial Translocation of an Activated MAP Kinase in Injured Nerve , 2005, Neuron.

[35]  J. Haugh,et al.  PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk , 2009, Molecular systems biology.

[36]  W. C. Finney,et al.  Brownian Diffusion and Surface Kinetics of Liposome and Viral Particle Uptake by Human Lung Cancer Cells In-Vitro , 2006, Annals of Biomedical Engineering.

[37]  B N Kholodenko,et al.  Spatial gradients of cellular phospho‐proteins , 1999, FEBS letters.

[38]  S. Rizzoli,et al.  Kiss‐and‐run, Collapse and ‘Readily Retrievable’ Vesicles , 2007, Traffic.

[39]  R. Campenot,et al.  Spatial requirements for TrkA kinase activity in the support of neuronal survival and axon growth in rat sympathetic neurons , 2003, Neuropharmacology.

[40]  C. Marshall,et al.  Specificity of receptor tyrosine kinase signaling: Transient versus sustained extracellular signal-regulated kinase activation , 1995, Cell.

[41]  H. Steven Wiley,et al.  Receptor downregulation and desensitization enhance the information processing ability of signalling receptors , 2007, BMC Syst. Biol..

[42]  Xuejun Jiang,et al.  Coordinated traffic of Grb2 and Ras during epidermal growth factor receptor endocytosis visualized in living cells. , 2002, Molecular biology of the cell.

[43]  D. Lauffenburger,et al.  Computational modeling of the EGF-receptor system: a paradigm for systems biology. , 2003, Trends in cell biology.

[44]  H. Wiley,et al.  The endocytotic rate constant. A cellular parameter for quantitating receptor-mediated endocytosis. , 1982, The Journal of biological chemistry.

[45]  Roger L. Williams,et al.  The emerging shape of the ESCRT machinery , 2007, Nature Reviews Molecular Cell Biology.

[46]  Andrew J. Lindsay,et al.  Rab-coupling protein coordinates recycling of α5β1 integrin and EGFR1 to promote cell migration in 3D microenvironments , 2008, The Journal of cell biology.

[47]  Chris Sander,et al.  Signal Processing in the TGF-β Superfamily Ligand-Receptor Network , 2005, PLoS Comput. Biol..

[48]  H. M. Byrne,et al.  Mathematical Model for Low Density Lipoprotein (LDL) Endocytosis by Hepatocytes , 2008, Bulletin of mathematical biology.

[49]  P. Camilli,et al.  Endocytosis and Signaling An Inseparable Partnership , 2001, Cell.

[50]  M. von Zastrow,et al.  Signaling on the endocytic pathway. , 2007, Current opinion in cell biology.

[51]  D. Lauffenburger,et al.  Parsing ERK Activation Reveals Quantitatively Equivalent Contributions from Epidermal Growth Factor Receptor and HER2 in Human Mammary Epithelial Cells* , 2005, Journal of Biological Chemistry.

[52]  W. Kolch Coordinating ERK/MAPK signalling through scaffolds and inhibitors , 2005, Nature Reviews Molecular Cell Biology.

[53]  C. M. Roth Molecular and cellular barriers limiting the effectiveness of antisense oligonucleotides. , 2005, Biophysical journal.

[54]  Boris N Kholodenko,et al.  MAP kinase cascade signaling and endocytic trafficking: a marriage of convenience? , 2002, Trends in cell biology.

[55]  Linda Hicke,et al.  Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. , 2003, Annual review of cell and developmental biology.

[56]  M. Miączyńska,et al.  Endocytic proteins in the regulation of nuclear signaling, transcription and tumorigenesis , 2009, Molecular oncology.

[57]  M. Eisenstein,et al.  Vimentin binding to phosphorylated Erk sterically hinders enzymatic dephosphorylation of the kinase. , 2006, Journal of molecular biology.

[58]  Z Bajzer,et al.  Binding, internalization, and intracellular processing of proteins interacting with recycling receptors. A kinetic analysis. , 1989, The Journal of biological chemistry.

[59]  T. Iga,et al.  Kinetic analysis of receptor-mediated endocytosis of epidermal growth factor by isolated rat hepatocytes. , 1991, The American journal of physiology.

[60]  H. Steven Wiley,et al.  A steady state model for analyzing the cellular binding, internalization and degradation of polypeptide ligands , 1981, Cell.

[61]  Eugenio Marco,et al.  Endocytosis Optimizes the Dynamic Localization of Membrane Proteins that Regulate Cortical Polarity , 2007, Cell.

[62]  H. J. Harwood,et al.  Kinetics of low-density lipoprotein receptor activity in Hep-G2 cells: derivation and validation of a Briggs-Haldane-based kinetic model for evaluating receptor-mediated endocytotic processes in which receptors recycle. , 1997, The Biochemical journal.

[63]  D. Lauffenburger,et al.  Computational modelling of ErbB family phosphorylation dynamics in response to transforming growth factor alpha and heregulin indicates spatial compartmentation of phosphatase activity. , 2006, Systems biology.

[64]  F. Orsenigo,et al.  Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments , 2006, The Journal of cell biology.

[65]  H. Wiley,et al.  An integrated model of epidermal growth factor receptor trafficking and signal transduction. , 2003, Biophysical journal.

[66]  J. Hancock,et al.  Ras proteins: different signals from different locations , 2003, Nature Reviews Molecular Cell Biology.

[67]  H. Pelham,et al.  Slow Diffusion of Proteins in the Yeast Plasma Membrane Allows Polarity to Be Maintained by Endocytic Cycling , 2003, Current Biology.

[68]  Xuejun Jiang,et al.  Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. , 2006, Molecular cell.

[69]  E. Gilles,et al.  Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors , 2002, Nature Biotechnology.

[70]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[71]  H. Wiley,et al.  Anomalous binding of epidermal growth factor to A431 cells is due to the effect of high receptor densities and a saturable endocytic system , 1988, The Journal of cell biology.

[72]  D A Lauffenburger,et al.  Effect of epidermal growth factor receptor internalization on regulation of the phospholipase C-gamma1 signaling pathway. , 1999, The Journal of biological chemistry.

[73]  M. Birnbaum,et al.  Kinetic analysis of glucose transporter trafficking in fibroblasts and adipocytes. , 1995, Biochemistry.

[74]  K Dane Wittrup,et al.  Quantitative spatiotemporal analysis of antibody fragment diffusion and endocytic consumption in tumor spheroids. , 2008, Cancer research.

[75]  Murat Cirit,et al.  PI3K-dependent cross-talk interactions converge with Ras as quantifiable inputs integrated by Erk , 2011, Molecular Systems Biology.

[76]  M. Bretscher Distribution of receptors for transferrin and low density lipoprotein on the surface of giant HeLa cells. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[77]  H. Steven Wiley,et al.  Cell Surface Receptors for Signal Transduction and Ligand Transport: A Design Principles Study , 2007, PLoS Comput. Biol..

[78]  K. Wittrup,et al.  Effect of antigen turnover rate and expression level on antibody penetration into tumor spheroids , 2008, Molecular Cancer Therapeutics.

[79]  B. Kholodenko Four-dimensional organization of protein kinase signaling cascades: the roles of diffusion, endocytosis and molecular motors , 2003, Journal of Experimental Biology.

[80]  B. Kholodenko Cell-signalling dynamics in time and space , 2006, Nature Reviews Molecular Cell Biology.

[81]  Boris N Kholodenko,et al.  Long-range signaling by phosphoprotein waves arising from bistability in protein kinase cascades , 2006, Molecular systems biology.

[82]  Alan Wells,et al.  Effect of Epidermal Growth Factor Receptor Internalization on Regulation of the Phospholipase C-γ1 Signaling Pathway* , 1999, The Journal of Biological Chemistry.

[83]  J. Kaplan,et al.  Mitogenic agents induce redistribution of transferrin receptors from internal pools to the cell surface. , 1986, The Biochemical journal.

[84]  Arwyn Tomos Jones,et al.  Macropinocytosis: searching for an endocytic identity and role in the uptake of cell penetrating peptides , 2007, Journal of cellular and molecular medicine.

[85]  H. Wiley,et al.  Receptor-mediated endocytosis in Xenopus oocytes. II. Evidence for two novel mechanisms of hormonal regulation. , 1987, The Journal of biological chemistry.

[86]  H. Wiley,et al.  Quantitative analysis of the endocytic system involved in hormone-induced receptor internalization. , 1990, The Journal of biological chemistry.

[87]  G. Scita,et al.  Endocytosis and spatial restriction of cell signaling , 2009, Molecular oncology.

[88]  K A Overholser,et al.  Rate constants for binding, dissociation, and internalization of EGF: effect of receptor occupancy and ligand concentration. , 1990, Biochemistry.

[89]  C Kaether,et al.  Microtubule-dependent transport of secretory vesicles visualized in real time with a GFP-tagged secretory protein. , 1997, Journal of cell science.