Signal 1

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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 the following two lectures look in detail at some specific examples of signaling pathways.

Note that you have already been introduced to signaling in many of your other lecture topics (searching PubMed for "cell signaling" gives 315,595 results).


Note - Stem Cell Practical - Exercise

2016 Lab 11

As part of the assessment for this course, your group will give a 15 minutes journal club presentation during the Lab on 26 May. For this you will have to discuss a recent (published after 2011) original research article on stem cell biology or technology, regenerative medicine, or stem cell therapy published in a high quality international research journal. Please note, reviews are not allowed.

Please search on PubMed for 2-3 research articles using search relevant terms, and send their PDFs to Annemiek (A.Beverdam@unsw.edu.au) by 5 pm on Wednesday 18 May. She will inform you which of the chosen articles are best suitable for presentation by Friday 20 May latest. Please note that the most exciting research articles are found in journals such as Nature, Science, Cell, Cell Stem Cell, etc. Please contact Annemiek in case you are at a loss, and she will help you find one.

During the presentation it works best if one student discusses the introduction, the second the results section, and the third the discussion section. Please note that one slide takes about 1 minute to talk through. So do not use more than 15 slides total. Please read through attached document for tips for how to prepare a good presentation. To make the Lab more interactive, I expect that each group will ask at least one question after each presentation.

You will receive a group mark based on presentation content, insight and comprehension, presentation and slide style, keeping within time, and contribution to discussion and questions.

Search PubMed: stem cell



Archive: 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

Search Online Textbooks

Books

PubMed

  • PubMed is a service of the U.S. National Library of Medicine that includes over 18 million citations from MEDLINE and other life science journals for biomedical articles back to 1948. PubMed includes links to full text articles and other related resources. PubMed
  • PubMed Central (PMC) is a free digital archive of biomedical and life sciences journal literature at the U.S. National Institutes of Health (NIH) in the National Library of Medicine (NLM) allowing all users free access to the material in PubMed Central. PMC
  • 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

Search Pubmed

Reviews

<pubmed>23838532</pubmed> <pubmed>21346732</pubmed> <pubmed>18396093</pubmed>| PMC <pubmed>18163464</pubmed>] <pubmed>17189856</pubmed> <pubmed>17630848</pubmed>

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.


2016 Course Content

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 | 2016 Revision


Laboratories: Introduction to Lab | Microscopy Methods | Preparation/Fixation | Cell Knockout Methods | Cytoskeleton Exercise | Immunochemistry | Project Work | Confocal Microscopy | Tissue Culture | Stem Cells Lab | Microarray Visit


2016 Projects: Group 1 | Group 2 | Group 3 | Group 4 | Group 5 | Group 6 | Group 7

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