2010 Lecture 19

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.

2009 lecture 2008: ANAT3231 Lecture 18-19 Cell Signaling

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 Movie - Extracellular Signaling

• Endocrine
  • Hormone (at a distance)
• Paracrine
  • Locally
• Neurotransmitter
  • Specific form of paracrine
• Autocrine
• Local (self)
• Contact Dependent

• 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
• Adhesion - Adherens Junction Dynamics

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 Signal Transduction Model Signaling between Tissues Regulation of cells and tissues

Hormones secreted by one tissue to regulate function of other cells or tissues

Chemical Signal Types

• water soluble
• lipid soluble

Movie: Hormone Signaling

Extracellular Signal Steps

• Signaling Molecule
• Synthesis
• Release by signaling cell
• Transport to target cell
• Detection by a specific receptor protein
• Change by receptor-signal complex (trigger)

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

cAMP molecular structure

Cyclic guanosine monophosphate (cGMP)

• Cyclic nucleotides
  • cAMP, cGMP
• Calcium Ions
• Protein Kinase A
  • PKA, B, C
• diacylglycerol (DAG)
  • modified lipid activates PKC
• 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 | View Movie: Second Messengers in Signaling Pathways

Steroid Responses

Steroid hormone receptor signaling

Steroidogenesis

• Intracellular Receptors
• Steroid Hormones
  • MCB - Steroid Hormones, Thyroxine, and Retinoic Acid | Cell - Structure of steroid hormones, thyroid hormone, vitamin D 3, and retinoic acid
  • thyroxine
  • vitamin D3
  • retinoic acid
  • estrogens and testosterone (derivatives of cholesterol)

Steroid_signaling_cartoon

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

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)

48 human nuclear receptor types

Steroid hormone receptor family

• 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

Steroid Receptors

• 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

Types

• 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

Eicosanoids

• lipids acting as signaling molecules
• act by binding to cell surface receptors
  • prostaglandins, prostacyclin, thromboxanes, and leukotrienes
• rapidly broken down
• act locally in autocrine or paracrine signaling pathways
• synthesized from arachidonic acid

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

Reviews

• The great divide: coordinating cell cycle events during bacterial growth and division. Haeusser DP, Levin PA. Curr Opin Microbiol. 2008 Apr;11(2):94-9. Epub 2008 Apr 7. Review. PMID: 18396093 | PMC

• Cell cycle studies based upon quantitative image analysis. Stacey DW, Hitomi M. Cytometry A. 2008 Apr;73(4):270-8. Review. PMID: 18163464

• Analysis of cell cycle phases and progression in cultured mammalian cells. Schorl C, Sedivy JM. Methods. 2007 Feb;41(2):143-50. Review. PMID: 17189856

• Cell cycle regulation of DNA replication. Sclafani RA, Holzen TM. Annu Rev Genet. 2007;41:237-80. Review. PMID: 17630848

Links

• Nature Signaling Gateway
• Cell Signaling Com - Pathways
• NURSA - Nuclear Receptor Signaling: Concepts and Models

2010 Course Content

Lectures: Cell Biology Introduction | Cells Eukaryotes and Prokaryotes | Cell Membranes and Compartments | Cell Nucleus | Cell Export - Exocytosis | Cell Import - Endocytosis | Cell Mitochondria | Cell Junctions | Cytoskeleton Introduction | Cytoskeleton 1 Intermediate Filaments | Cytoskeleton 2 Microtubules | Cytoskeleton 3 Microfilaments | 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 | Revision

Laboratories: Introduction to Lab | Microscopy Methods | Preparation/Fixation | Immunochemistry | Cell Knockout Methods | Cytoskeleton Exercise | Confocal Microscopy | Microarray Visit | Tissue Culture 1 | Tissue Culture 2 | Stem Cells Lab | Stem Cells Analysis

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