Signal 1

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

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

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 (cAMP)

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

Intracellular Receptors (longest acting of hormone classes, hours-days) Steroid Hormones (androgens, glucocorticoids, mineralocorticoids) MCB - Steroid Hormones, Thyroxine, and Retinoic Acid | Cell - Structure of steroid hormones, thyroid hormone, vitamin D 3, and retinoic acid thyroxine (thyroid, not a steroid) vitamin D3 retinoic acid cortisol (adrenal) estrogens and testosterone (gonad) All steroid hormones are synthesized from cholesterol. Steroid hormones are less soluble in aqueous solution, most in blood as complexes bound to specific plasma globulins or albumin (synthesised in the liver)

Steroid_signaling_cartoon

Other Endocrine Axes

• 

  Hypothalamus - Pituitary - Adrenal

• 

  Hypothalamus - Pituitary - Thyroid

• 

  Hypothalamus - Pituitary - Gonad (female)

• 

  Hypothalamus - Pituitary - Gonad (male)

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 Biology of the Cell 4th ed. - IV. Internal Organization of the Cell Chapter 15. Cell Communication
• Cell Communication
• General Principles of Cell Communication
• Figure 15-12. Some signaling molecules that bind to nuclear receptors

Molecular Cell Biology

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

• Molecular Cell Biology - Chapter 20. Cell-to-Cell Signaling: Hormones and Receptors
• Cell-to-Cell Signaling: Hormones and Receptors
• Overview of Extracellular Signaling
• Steroid Hormones, Thyroxine, and Retinoic Acid
• Table 20-1. Characteristic Properties of Principal Types of Mammalian Hormones
• Figure 20-6. Schematic overview of common signaling pathways downstream from G protein–coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs)

The Cell- A Molecular Approach

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

• The Cell - A Molecular Approach - IV. Cell Regulation Chapter 13. Cell Signaling
• Cell Signaling
• Modes of Cell-Cell Signaling
• Figure 13.2. Structure of steroid hormones, thyroid hormone, vitamin D 3, and retinoic acid
• Figure 13.3. Action of steroid hormones

Search Online Textbooks

• "cell signaling" Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach | Bookshelf

• "steroid signaling" Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach | Bookshelf

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

• "cell signaling" Entrez all databases
• "steroid signaling" Entrez all databases | images

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

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.

• Nature Signaling Gateway
• Cell Signaling Com - Pathways
• NURSA - Nuclear Receptor Signaling: Concepts and Models
• Cell Signaling Technology - Chromatin/Epigenetics | MAPK Signaling | Apoptosis/Autophagy | PI3K/Akt Signaling | Translational Control | Ca, cAMP & Lipid Signaling | Cell Cycle/Checkpoint | DNA Damage | Jak/Stat Pathway | NF-κB Signaling | TGF-β/Smad Signaling | Lymphocyte Signaling | Neuroscience | Angiogenesis | Vesicle Trafficking | Cytoskeletal Signaling | Adhesion | Glucose Metabolism | Wnt/Hedgehog/Notch | Protein Folding | Protein Stability
• Abcam signaling tools

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