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 448,244 results).

Archive: 2010 lecture | 2009 lecture | 2008 lecture

Movie - Neutrophil chasing Bacterium

iLecture: Lecture 17 Audio

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 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

Synthesis
Release by signaling cell
Transport to target cell
Detection by a specific receptor protein
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)
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

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

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

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

Reviews

Ugo Cavallaro, Elisabetta Dejana Adhesion molecule signalling: not always a sticky business. Nat. Rev. Mol. Cell Biol.: 2011, 12(3);189-97 PMID: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 PMID:18396093 | PMC Dennis W Stacey, Masahiro Hitomi Cell cycle studies based upon quantitative image analysis. Cytometry A: 2008, 73(4);270-8 PMID:18163464 ] Christoph Schorl, John M Sedivy Analysis of cell cycle phases and progression in cultured mammalian cells. Methods: 2007, 41(2);143-50 PMID:17189856

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

2012 Course Content

Dr Mark Hill 2013, UNSW Cell Biology - UNSW CRICOS Provider Code No. 00098G

Signal 1

Contents