Divergent Dynamics and Functions of ERK MAP Kinase Signaling in Development, Homeostasis and Cancer: Lessons from Fluorescent Bioimaging

The extracellular signal-regulated kinase (ERK) signaling pathway regulates a variety of biological processes including cell proliferation, survival, and differentiation. Since ERK activation promotes proliferation of many types of cells, its deregulated/constitutive activation is among general mechanisms for cancer. Recent advances in bioimaging techniques have enabled to visualize ERK activity in real-time at the single-cell level. Emerging evidence from such approaches suggests unexpectedly complex spatiotemporal dynamics of ERK activity in living cells and animals and their crucial roles in determining cellular responses. In this review, we discuss how ERK activity dynamics are regulated and how they affect biological processes including cell fate decisions, cell migration, embryonic development, tissue homeostasis, and tumorigenesis.

[1]  Ying Xu,et al.  ERK/MAPK signalling pathway and tumorigenesis , 2020, Experimental and therapeutic medicine.

[2]  A. Ivanov,et al.  A Septin Cytoskeleton-Targeting Small Molecule, Forchlorfenuron, Inhibits Epithelial Migration via Septin-Independent Perturbation of Cellular Signaling , 2019, Cells.

[3]  L. Skalniak,et al.  Helping the Released Guardian: Drug Combinations for Supporting the Anticancer Activity of HDM2 (MDM2) Antagonists , 2019, Cancers.

[4]  Y. Bessho,et al.  ERK Activity Dynamics during Zebrafish Embryonic Development , 2018, International journal of molecular sciences.

[5]  T. Abe,et al.  Live-Cell FRET Imaging Reveals a Role of Extracellular Signal-Regulated Kinase Activity Dynamics in Thymocyte Motility , 2018, iScience.

[6]  A. Sood,et al.  EGFL6 promotes breast cancer by simultaneously enhancing cancer cell metastasis and stimulating tumor angiogenesis , 2018, Oncogene.

[7]  M. Distel,et al.  Fast Dynamic in vivo Monitoring of Erk Activity at Single Cell Resolution in DREKA Zebrafish , 2018, Front. Cell Dev. Biol..

[8]  Jared E. Toettcher,et al.  Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway , 2018, Science.

[9]  T. Shibata,et al.  A Switch-like Activation Relay of EGFR-ERK Signaling Regulates a Wave of Cellular Contractility for Epithelial Invagination. , 2018, Developmental cell.

[10]  Y. Zeng,et al.  TNFRSF19 Inhibits TGFβ Signaling through Interaction with TGFβ Receptor Type I to Promote Tumorigenesis. , 2018, Cancer research.

[11]  H. Seno,et al.  Composite regulation of ERK activity dynamics underlying tumour-specific traits in the intestine , 2018, Nature Communications.

[12]  Sohum Mehta,et al.  Live‐cell imaging of cell signaling using genetically encoded fluorescent reporters , 2018, The FEBS journal.

[13]  J. Eschbacher,et al.  A Novel Signaling Complex between TROY and EGFR Mediates Glioblastoma Cell Invasion , 2017, Molecular Cancer Research.

[14]  Kazuhiro Aoki,et al.  Propagating Wave of ERK Activation Orients Collective Cell Migration. , 2017, Developmental cell.

[15]  I. Greenwald,et al.  A Real-Time Biosensor for ERK Activity Reveals Signaling Dynamics during C. elegans Cell Fate Specification. , 2017, Developmental cell.

[16]  Maxwell Z. Wilson,et al.  Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control. , 2017, Molecular cell.

[17]  E. Nishida,et al.  Antagonistic Interactions between Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and Retinoic Acid Receptor Signaling in Colorectal Cancer Cells , 2017, Molecular and Cellular Biology.

[18]  Lu Wang,et al.  Mechanisms of resistance to anti-EGFR therapy in colorectal cancer , 2016, Oncotarget.

[19]  E. Yoon,et al.  EGFL6 Regulates the Asymmetric Division, Maintenance, and Metastasis of ALDH+ Ovarian Cancer Cells. , 2016, Cancer research.

[20]  Jurgen Müller,et al.  Negative feedback regulation of the ERK1/2 MAPK pathway , 2016, Cellular and Molecular Life Sciences.

[21]  Sophie Dahan,et al.  Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction. , 2016, Annual review of biochemistry.

[22]  Michael Pargett,et al.  Receptor Level Mechanisms Are Required for Epidermal Growth Factor (EGF)-stimulated Extracellular Signal-regulated Kinase (ERK) Activity Pulses* , 2015, The Journal of Biological Chemistry.

[23]  X. Guan,et al.  Abstract 118: EGFL6, a potential novel ligand of EGFR, play roles in Nasopharyngeal cacinoma metastasis through establishing invasive and long-distant metastatic niche by paracrine and autocrine , 2015 .

[24]  Atsushi Miyawaki,et al.  Molecular spies for bioimaging--fluorescent protein-based probes. , 2015, Molecular cell.

[25]  Honda Naoki,et al.  Intercellular propagation of extracellular signal-regulated kinase activation revealed by in vivo imaging of mouse skin , 2015, eLife.

[26]  P. Poulikakos,et al.  Targeting RAS–ERK signalling in cancer: promises and challenges , 2014, Nature Reviews Drug Discovery.

[27]  Jacob J. Hughey,et al.  High-Sensitivity Measurements of Multiple Kinase Activities in Live Single Cells , 2014, Cell.

[28]  K. Sumiyama,et al.  In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines , 2014, The Journal of experimental medicine.

[29]  Kazuhiro Aoki,et al.  Stochastic ERK activation induced by noise and cell-to-cell propagation regulates cell density-dependent proliferation. , 2013, Molecular cell.

[30]  J. Eschbacher,et al.  TROY (TNFRSF19) Promotes Glioblastoma Survival Signaling and Therapeutic Resistance , 2013, Molecular Cancer Research.

[31]  Kazuhiro Aoki,et al.  Fluorescence resonance energy transfer imaging of cell signaling from in vitro to in vivo: Basis of biosensor construction, live imaging, and image processing , 2013, Development, growth & differentiation.

[32]  K. Kinzler,et al.  Cancer Genome Landscapes , 2013, Science.

[33]  John G. Albeck,et al.  Frequency-modulated pulses of ERK activity transmit quantitative proliferation signals. , 2013, Molecular cell.

[34]  Bruce J. Aronow,et al.  The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor , 2012, Cell.

[35]  Hans Clevers,et al.  Lrig1 controls intestinal stem cell homeostasis by negative regulation of ErbB signalling , 2012, Nature Cell Biology.

[36]  Kazuhiro Aoki,et al.  Development of an optimized backbone of FRET biosensors for kinases and GTPases , 2011, Molecular biology of the cell.

[37]  Rony Seger,et al.  The ERK Cascade: Distinct Functions within Various Subcellular Organelles. , 2011, Genes & cancer.

[38]  Yosef Yarden,et al.  Feedback regulation of EGFR signalling: decision making by early and delayed loops , 2011, Nature Reviews Molecular Cell Biology.

[39]  N. Tran,et al.  TROY (TNFRSF19) Is Overexpressed in Advanced Glial Tumors and Promotes Glioblastoma Cell Invasion via Pyk2-Rac1 Signaling , 2010, Molecular Cancer Research.

[40]  F. Ye,et al.  Inhibition of LRIG3 gene expression via RNA interference modulates the proliferation, cell cycle, cell apoptosis, adhesion and invasion of glioblastoma cell (GL15). , 2009, Cancer Letters.

[41]  K. Svoboda,et al.  A genetically encoded fluorescent sensor of ERK activity , 2008, Proceedings of the National Academy of Sciences.

[42]  Rony Seger,et al.  The MEK/ERK cascade: from signaling specificity to diverse functions. , 2007, Biochimica et biophysica acta.

[43]  S. Halegoua,et al.  Trk-signaling endosomes are generated by Rac-dependent macroendocytosis , 2007, Proceedings of the National Academy of Sciences.

[44]  P. Bastiaens,et al.  Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate , 2007, Nature Cell Biology.

[45]  C. Klein,et al.  p14–MP1-MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis , 2006, The Journal of cell biology.

[46]  Miki Ebisuya,et al.  Continuous ERK Activation Downregulates Antiproliferative Genes throughout G1 Phase to Allow Cell-Cycle Progression , 2006, Current Biology.

[47]  J. Blenis,et al.  MAPK signal specificity: the right place at the right time. , 2006, Trends in biochemical sciences.

[48]  Yoshiki Tsuchiya,et al.  Regulatory mechanisms and functions of MAP kinase signaling pathways , 2006, IUBMB life.

[49]  Kunio Kondoh,et al.  The duration, magnitude and compartmentalization of ERK MAP kinase activity: mechanisms for providing signaling specificity , 2005, Journal of Cell Science.

[50]  K. Kinzler,et al.  Somatic mutations of EGFR in colorectal cancers and glioblastomas. , 2004, The New England journal of medicine.

[51]  E. Nishida,et al.  Sef is a spatial regulator for Ras/MAP kinase signaling. , 2004, Developmental cell.

[52]  Miki Ebisuya,et al.  ERK Activation Propagates in Epithelial Cell Sheets and Regulates Their Migration during Wound Healing , 2004, Current Biology.

[53]  C. Marshall,et al.  Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells , 2003, Journal of Cell Science.

[54]  Richard Wooster,et al.  BRAF and RAS mutations in human lung cancer and melanoma. , 2002, Cancer research.

[55]  D. Teis,et al.  Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction. , 2002, Developmental cell.

[56]  E. Nishida,et al.  Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway , 2002, Nature Cell Biology.

[57]  Hans Clevers,et al.  The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells , 2002, Cell.

[58]  K. Kinzler,et al.  Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status , 2002, Nature.

[59]  Rey-Huei Chen,et al.  Molecular interpretation of ERK signal duration by immediate early gene products , 2002, Nature Cell Biology.

[60]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[61]  R. Germain.  T-cell development and the CD4–CD8 lineage decision , 2002, Nature Reviews Immunology.

[62]  D. Morrison,et al.  C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. , 2001, Molecular cell.

[63]  David C. Lee,et al.  Growth retardation, duodenal lesions, and aberrant ileum architecture in triple null mice lacking EGF, amphiregulin, and TGF-alpha. , 2001, Gastroenterology.

[64]  Walter Kolch,et al.  Identification of the Mechanisms Regulating the Differential Activation of the MAPK Cascade by Epidermal Growth Factor and Nerve Growth Factor in PC12 Cells* , 2001, The Journal of Biological Chemistry.

[65]  M. Cobb,et al.  Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. , 2001, Endocrine reviews.

[66]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[67]  A. Pfeifer,et al.  A Novel 14-Kilodalton Protein Interacts with the Mitogen-Activated Protein Kinase Scaffold Mp1 on a Late Endosomal/Lysosomal Compartment , 2001, The Journal of cell biology.

[68]  E. Mccleskey,et al.  Rap1 mediates sustained MAP kinase activation induced by nerve growth factor , 1998, Nature.

[69]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[70]  R. Derynck,et al.  Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor , 1995, Nature.

[71]  M Oshima,et al.  Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[72]  C. Slaughter,et al.  ERK phosphorylation potentiates Elk‐1‐mediated ternary complex formation and transactivation. , 1995, The EMBO journal.

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

[74]  P. Cohen,et al.  EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor , 1994, Current Biology.

[75]  E. Van Obberghen,et al.  Co-regulation of the mitogen-activated protein kinase, extracellular signal-regulated kinase 1, and the 90-kDa ribosomal S6 kinase in PC12 cells. Distinct effects of the neurotrophic factor, nerve growth factor, and the mitogenic factor, epidermal growth factor. , 1993, The Journal of biological chemistry.

[76]  E. Nishida,et al.  The MAP kinase cascade is essential for diverse signal transduction pathways. , 1993, Trends in biochemical sciences.

[77]  E. Nishida,et al.  Microtubule-associated-protein (MAP) kinase activated by nerve growth factor and epidermal growth factor in PC12 cells. Identity with the mitogen-activated MAP kinase of fibroblastic cells. , 1990, European journal of biochemistry.

[78]  B. Vogelstein,et al.  A genetic model for colorectal tumorigenesis , 1990, Cell.

[79]  G. Guroff,et al.  Nerve growth factor-induced alteration in the response of PC12 pheochromocytoma cells to epidermal growth factor , 1981, The Journal of cell biology.

[80]  L. Greene,et al.  Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[81]  R. Henriksson,et al.  Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma. , 2013, International journal of oncology.

[82]  K. Sumiyama,et al.  Live imaging of protein kinase activities in transgenic mice expressing FRET biosensors. , 2012, Cell structure and function.

[83]  E. Nishida,et al.  Regulation of ERK activity duration by Sprouty contributes to dorsoventral patterning , 2009, Nature Cell Biology.