Signal 1

From CellBiology

Cell Signaling 1

This lecture is an introduction to a series of lectures on cell signaling. The first lecture is a general introduction to the different signaling mechanisms and second messengers. The lecture will also describe the signaling pathways through cytoplasmic and nuclear steroid signaling pathway. The following lecture (2) looks in detail at some specific examples of signaling pathways through membrane receptors.

Note that you have already been introduced to signaling in many of your other lecture topics.


Lecture Slides: 2017 Lecture PDF | 2017 Lecture PDF 4 slides/page


Note - The information shown on this page below is for background purposes only, the slides linked above will be used in this lecture presentation.


Archive: 2016 | 2015 | 2013 | 2010 lecture | 2009 lecture

Cells.jpg

Movie - Neutrophil chasing Bacterium

Objectives

  • Understand main types of signaling mechanisms
  • Understand concept of receptor and ligand
  • Understand membrane, cytoplasmic and nuclear receptors
  • Brief understanding of steroid hormone pathway
  • Brief understanding protein growth factor pathway
  • Understand differences between select membrane receptors (G protein structure, tyrosine kinases)

Lecture Summary

  • Messengers and Receptors
  • chemical signals
  • cellular receptors
  • signal transduction
  • intracellular pathways
  • second messengers
  • Examples of signaling

Signaling Mechanisms

MCB - Extracellular Signaling

  • Endocrine - Hormone (at a distance)
  • Paracrine - Locally
    • Neurotransmitter - Specific form of paracrine
  • Autocrine - Local (self)
    • Contact Dependent
Signal transduction pathways.png


Links: Cell - Modes of Cell-Cell Signaling | MCB - Cell-to-Cell Signaling: Hormones and Receptors | MCB - Overview of Extracellular Signaling | Cell - Cell Signaling | MCoB - Cell Communication | MCoB - General Principles of Cell Communication | Adherens Junction Dynamics | Commercial Database - Pathways

Cell Communication

  • Contact Mediated - display molecules on cell surface, recognized by receptor on another cell
  • Non-Contact Mediated - chemical signal, nearby or at a distance
  • Common Signals Signals and Receptors

Chemical Signal Types

  • water soluble
  • lipid soluble

Movie: Hormone Signaling

Extracellular Signal Steps

Signaling Molecule

  1. Synthesis
  2. Release by signaling cell
  3. Transport to target cell
  4. Detection by a specific receptor protein
  5. Change by receptor-signal complex (trigger)

There can also be a feedback mechanism following signaling.

Cell Surface Receptors

  • four main classes
    • G protein–coupled receptors
    • ion-channel receptors
    • receptors linked to cytosolic tyrosine kinases
    • receptors with intrinsic catalytic activity
  • ligand binding to cell-surface receptor
    • trigger intracellular pathways
    • modulate cellular metabolism, function, or development
  • Removal of the signal
    • often terminates cellular response

Second Messengers

Cyclic-adenosine-monophosphate-2D-skeletal.png

Cyclic adenosine monophosphate (cAMP)

Cyclic guanosine monophosphate.png

Cyclic guanosine monophosphate (cGMP)

  • Cyclic nucleotides - cAMP, cGMP (will cover also in next lecture G protein signalling)
  • Calcium Ions
  • Inositol 1,4,5-trisphosphate (IP3) (see also IP3 receptor PMID 9243320) IP3 receptor plays in the conversion of numerous external stimuli to intracellular Ca2+ signal
  • Diacylglycerol (DAG) - modified lipid activates PKC
  • Protein Kinase A - PKA, B, C (phosphorylate other proteins)
  • regulate the activity of cellular proteins (enzymes and non-enzymatic)

Links: Cell - Common intracellular signaling proteins Elevation of cytosolic Ca2+ via the inositol-lipid signaling pathway | Movie: Second Messengers in Signaling Pathways

Steroid Responses

Steroid hormone receptor signaling
Steroidogenesis
Hypothalamus endocrine system.jpg

Steroid_signaling_cartoon

Other Endocrine Axes


MCB - Characteristic Properties of Principal Types of Mammalian Hormones | MCoB - Some signaling molecules that bind to nuclear receptors | Cell - Action of steroid hormones

Steroid Hormone Receptors (SHRs)

Steroid hormone receptor signaling

Cytosol location

  • receptor bound to inhibitor
  • ligand binding activates receptor
  • translocates to nucleus on ligand binding

Nuclear location

  • binds ligand and DNA
  • becomes transcription factor
  • estrogen receptor, two forms ERα [NR3A1] and ERβ [NR3A2]
  • cortisol binding glucocorticoid receptor (GR) [NR3C1]
  • aldosterone binding mineralocorticoid receptor (MR) [NR3C2]
  • progesterone receptor (PR) [NR3C3]
  • dihydrotestosterone (DHT) binding androgen receptor (AR) [NR3C4]

Steroid_signaling_cartoon

Nuclear Receptor Signaling

Receptor Structure

Nuclear Receptor
  • steroid binding region - near C-terminus
  • DNA binding - central region
    • zinc finger motif
    • alpha helix and 2 beta sheets held in place by cysteine or histidine residues by a zinc atom
    • multiple fingers typical
  • DNA response element
  • Enhancer
Links: Box 1.12Steroid receptors, zinc fingers and DNA binding

Receptor Types

48 human nuclear receptor types

Steroid hormone receptor family
  • Type I Receptors
    • Sex hormone receptors (sex hormones) - Androgen receptor, Estrogen receptor, Progesterone receptor
    • Glucocorticoid receptor (glucocorticoids)
    • Mineralocorticoid receptor (mineralocorticoids)
  • Type II Receptors
    • Vitamin A receptor
    • Vitamin D receptor
    • Retinoid receptor
    • Thyroid hormone receptor
  • Orphan receptors
Links: nuclear-receptor superfamily three classes | Image - Models of sex steroid action in target tissue

Eicosanoids

  • (icosanoids) prostaglandins, prostacyclins, thromboxanes and leukotrienes
  • lipids acting as signaling molecules
    • made from essential fatty acids (EFAs) oxidation (arachidonic acid)
  • act by binding to cell surface receptors, rapidly broken down (anti-inflammatory drugs act by downregulating eicosanoid synthesis)
  • act locally in autocrine or paracrine signaling pathways


Links: Eicosanoid biosynthesis cartoon | Prostaglandins

Nitric Oxide

  • (nitrogen monoxide) another signaling method that crosses lipid membranes
  • simple gas, very quick short-lived signal
    • synthesised from arginine by nitric oxide synthase
  • does not bind intracellular receptor
    • regulates intracellular enzymes

Example - dilation of blood vessels. (nitroglycerine for heart converted to NO)

References

Textbooks

Essential Cell Biology

  • Essential Cell Biology Chapter 15

Molecular Biology of the Cell

Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002

Molecular Cell Biology

Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999

The Cell- A Molecular Approach

Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000

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Books

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  • Online Mendelian Inheritance in Man (OMIM) is a comprehensive compendium of human genes and genetic phenotypes. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and over 12,000 genes. OMIM
  • Entrez is the integrated, text-based search and retrieval system used at NCBI for the major databases, including PubMed, Nucleotide and Protein Sequences, Protein Structures, Complete Genomes, Taxonomy, and others Entrez

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Reviews

Lindsey S Treviño, Nancy L Weigel Phosphorylation: a fundamental regulator of steroid receptor action. Trends Endocrinol. Metab.: 2013, 24(10);515-24 PubMed 23838532

Ugo Cavallaro, Elisabetta Dejana Adhesion molecule signalling: not always a sticky business. Nat. Rev. Mol. Cell Biol.: 2011, 12(3);189-97 PubMed 21346732

Daniel P Haeusser, Petra Anne Levin The great divide: coordinating cell cycle events during bacterial growth and division. Curr. Opin. Microbiol.: 2008, 11(2);94-9 PubMed 18396093

| PMC Dennis W Stacey, Masahiro Hitomi Cell cycle studies based upon quantitative image analysis. Cytometry A: 2008, 73(4);270-8 PubMed 18163464

] Christoph Schorl, John M Sedivy Analysis of cell cycle phases and progression in cultured mammalian cells. Methods: 2007, 41(2);143-50 PubMed 17189856

R A Sclafani, T M Holzen Cell cycle regulation of DNA replication. Annu. Rev. Genet.: 2007, 41;237-80 PubMed 17630848


Articles

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name.


2017 Course Content

Moodle

Lectures: Cell Biology Introduction | Cells Eukaryotes and Prokaryotes | Cell Membranes and Compartments | Cell Nucleus | Cell Export - Exocytosis | Cell Import - Endocytosis | Cytoskeleton Introduction | Cytoskeleton - Microfilaments | Cytoskeleton - Microtubules | Cytoskeleton - Intermediate Filaments | Cell Mitochondria | Cell Junctions | Extracellular Matrix 1 | Extracellular Matrix 2 | Cell Cycle | Cell Division | Cell Death 1 | Cell Death 2 | Signal 1 | Signal 2 | Stem Cells 1 | Stem Cells 2 | Development | 2017 Revision

2017 Laboratories: Introduction to Lab | Fixation and Staining |


2017 Projects: Group 1 - Delta | Group 2 - Duct | Group 3 - Beta | Group 4 - Alpha

Dr Mark Hill 2015, UNSW Cell Biology - UNSW CRICOS Provider Code No. 00098G