title: Regulation of ERK-MAPK signaling in human epidermis.
abstract: BACKGROUND
  The skin is largely comprised of keratinocytes within the interfollicular epidermis. Over approximately two weeks these cells differentiate and traverse the thickness of the skin. The stage of differentiation is therefore reflected in the positions of cells within the tissue, providing a convenient axis along which to study the signaling events that occur in situ during keratinocyte terminal differentiation, over this extended two-week timescale. The canonical ERK-MAPK signaling cascade (Raf-1, MEK-1/2 and ERK-1/2) has been implicated in controlling diverse cellular behaviors, including proliferation and differentiation. While the molecular interactions involved in signal transduction through this cascade have been well characterized in cell culture experiments, our understanding of how this sequence of events unfolds to determine cell fate within a homeostatic tissue environment has not been fully characterized.
  
  
  METHODS
  We measured the abundance of total and phosphorylated ERK-MAPK signaling proteins within interfollicular keratinocytes in transverse cross-sections of human epidermis using immunofluorescence microscopy. To investigate these data we developed a mathematical model of the signaling cascade using a normalized-Hill differential equation formalism.
  
  
  RESULTS
  These data show coordinated variation in the abundance of phosphorylated ERK-MAPK components across the epidermis. Statistical analysis of these data shows that associations between phosphorylated ERK-MAPK components which correspond to canonical molecular interactions are dependent upon spatial position within the epidermis. The model demonstrates that the spatial profile of activation for ERK-MAPK signaling components across the epidermis may be maintained in a cell-autonomous fashion by an underlying spatial gradient in calcium signaling.
  
  
  CONCLUSIONS
  Our data demonstrate an extended phospho-protein profile of ERK-MAPK signaling cascade components across the epidermis in situ, and statistical associations in these data indicate canonical ERK-MAPK interactions underlie this spatial profile of ERK-MAPK activation. Using mathematical modelling we have demonstrated that spatially varying calcium signaling components across the epidermis may be sufficient to maintain the spatial profile of ERK-MAPK signaling cascade components in a cell-autonomous manner. These findings may have significant implications for the wide range of cancer drugs which therapeutically target ERK-MAPK signaling components.
authors.affiliation: Systems Biology Laboratory, Melbourne School of Engineering, University of Melbourne, Melbourne, Australia. joseph.cursons@unimelb.edu.au.|NICTA Victoria Research Lab, Melbourne, Australia. joseph.cursons@unimelb.edu.au.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Melbourne School of Engineering, University of Melbourne, Melbourne, Australia. joseph.cursons@unimelb.edu.au.|Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand. joseph.cursons@unimelb.edu.au.|Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand. joseph.cursons@unimelb.edu.au.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cursons
authors.affiliation: Systems Biology Laboratory, Melbourne School of Engineering, University of Melbourne, Melbourne, Australia. jerry.gao@unimelb.edu.au.
authors.forename: Jerry
authors.initials: J
authors.lastname: Gao
authors.affiliation: Systems Biology Laboratory, Melbourne School of Engineering, University of Melbourne, Melbourne, Australia. daniel.hurley@unimelb.edu.au.|NICTA Victoria Research Lab, Melbourne, Australia. daniel.hurley@unimelb.edu.au.|Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand. daniel.hurley@unimelb.edu.au.|Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand. daniel.hurley@unimelb.edu.au.|Bioinformatics Institute, University of Auckland, Auckland, New Zealand. daniel.hurley@unimelb.edu.au.|Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. daniel.hurley@unimelb.edu.au.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Hurley
authors.affiliation: Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand. c.print@auckland.ac.nz.|Bioinformatics Institute, University of Auckland, Auckland, New Zealand. c.print@auckland.ac.nz.|Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. c.print@auckland.ac.nz.
authors.forename: Cristin G
authors.initials: CG
authors.lastname: Print
authors.affiliation: Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand. r.dunbar@auckland.ac.nz.|School of Biological Sciences, University of Auckland, Auckland, New Zealand. r.dunbar@auckland.ac.nz.
authors.forename: P Rod
authors.initials: PR
authors.lastname: Dunbar
authors.affiliation: Department of Biology, New Zealand International College, ACG New Zealand, Auckland, New Zealand. marc.jacobs@gmx.com.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Jacobs
authors.affiliation: Systems Biology Laboratory, Melbourne School of Engineering, University of Melbourne, Melbourne, Australia. edmund.crampin@unimelb.edu.au.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Melbourne School of Engineering, University of Melbourne, Melbourne, Australia. edmund.crampin@unimelb.edu.au.|Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand. edmund.crampin@unimelb.edu.au.|Maurice Wilkins Centre, University of Auckland, Auckland, New Zealand. edmund.crampin@unimelb.edu.au.|School of Mathematics and Statistics, University of Melbourne, Melbourne, Australia. edmund.crampin@unimelb.edu.au.|School of Medicine, University of Melbourne, Melbourne, Australia. edmund.crampin@unimelb.edu.au.
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Crampin
mesh_terms: D000078404:Epidermal Cells; D004817:Epidermis / Q000201:enzymology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases