1. Cell Signaling I Signaling molecules and their receptors
Cell Biology
Lecture 12

2. Readings and Objectives
Russell Chapter 8 (not sufficient)
Cooper: Chapter 15
Topics
Lecture 12
Signaling Molecules and Their Receptors
Functions of Cell Surface Receptors
Lecture 13
Pathways of Intracellular Signal Transduction
Signal Transduction and the Cytoskeleton
Signaling Networks

3. Cell Signaling Introduction
regulate virtually all aspects of cell behavior
Cell proliferation, metabolism, organellar and cell movement, apoptosis, etc
Modes of cell signaling
Direct cell-cell signaling—direct interaction of a cell with its neighbor
Signaling by secreted molecules—signals are transmitted over distant cells
signaling molecules from one cell bind to receptors on other cells
range in complexity from simple gases to proteins

4. Signaling by secreted molecules
Endocrine signaling—signaling molecules (hormones), target cells at distant body sites Example: estrogen.
Paracrine signaling—act on neighboring target cells, e.g., neurotransmitters
Autocrine signaling—respond to self signaling molecules
T lymphocytes: proliferation in response to cytokines produced by the same cell

5. Animation: Types of Signaling

6. Signaling molecules Classes of signaling molecules
Hydrophobic signaling molecules
Use nuclear receptors
Neurotransmitters
Peptide signaling molecuels
Eicosanoids
2 through 4 use membrane receptors

7. 1. Hydrophobic signaling molecules
Passively diffuse across cell membrane
Steroid hormones
Vitamin D3
Thyroid hormone
Retinoid acid
Nitric oxide and CO
All use intracellular receptors
function as activators or repressors of genes

8. 2. Neurotransmitters
carry signals between neurons, from neurons to other target cells
hydrophilic, can’t cross the plasma membrane of target cells; bind to cell surface receptors
receptors ligand-gated ion channels
Neurotranmitter binding opens the channels

9. 3. Peptide signaling molecules
Peptide hormones
Neuropeptides
polypeptide growth factors
Short polypeptides, one or more chains
Variety of functions
All use cell membrane anchored receptors

10. 4. Eicosanoids: lipid signaling molecules
Eicosanoids: lipid signaling molecules which include prostaglandins, prostacyclin, thromboxanes, and leukotrienes
Arachindonic derived from phospholipids, by phospholypase A2

11. 4. Peptide signaling molecules
Cyclooxygenases catalyse the conversion (targets for anti-inflammatory drugs)
Short lived, thus act in autocrine or paracrine pathways
Platelet aggregation, inflammation, smooth muscle contraction

12. Signaling Receptors Two types
Intracellular receptors: include nuclear receptor family
bind hydrophobic signaling ligands
Conformation change, translocate to nucleus
Act as transcriptional activators or repressors to regulate gene expression
Signal does not amplify
Membrane integral receptors:
Bind non-hydrophobic signaling ligands
Conformational change activates a phospho-relay cascade through kinases; might rely on secondary signaling molecules
Exponential signal amplification through kinase cascade
Targets: transcription, replication, translation, cytoskeleton remodeling, metabolic modulation, etc.

13. Animation: Signal amplification

14. Intracellular receptors: Nuclear Receptors
Nuclear receptor superfamily
Transcription factors, have domains for
ligand binding
DNA binding
modulate transcription transcriptional activators or repressors
Glucocorticoid receptor: bound to Hsp90 chaperones in the absence of hormone
Glucocorticoid binding displaces Hsp90; binds the regulatory DNA sequences together with HAT coactivator (Histon acetyl transferase)

15. Intracellular receptors: Nuclear Receptors
Thyroid hormone
Hormone binding may alter the activity of the receptor:
In the absence of hormone
hormone receptor is associated with a corepressor complex (HDAC)
No transcription of target genes
Hormone binding,
replaces HDAC with HAT (activator)
Transcription is activated

16. Membrane receptors: G-protein coupled receptros
largest family of cell surface receptors
seven membrane-spanning α helices
Various signaling ligands,
Hormones
neurotransmitters
Signals transmitted via guanine nucleotide-binding proteins (G proteins)
Various targets and effector proteins

17. Membrane receptors: G-protein coupled receptros
Ligand binding, conformational change, cytosolic domain activates a G protein
heterotrimeric G proteins : α, β, and γ subunits
α- binds G-nucleotides, regulate G protein activity
In inactive state, α bound to GDP in a complex with β, and γ
ligand binding causes GTP to replace GDP
The α and βγ complex then dissociate from the receptor and interact with their targets
A large array of G proteins connect receptors to distinct targets.
G proteins can also regulate ion channels

18. Animation: G-protein coupled receptors

19. Receptor Protein- Tyrosine Kinases
Humans have 59 receptor RPTK
Signaling molecules: EGF, NGF, PDGF, and other growth factors and insulin
phosphorylate their substrate proteins on tyrosine residues
Structure
N-terminal extracellular ligand-binding domain
single transmembrane α helix
a cytosolic C-terminal domain with protein-tyrosine kinase activity

20. Receptor Protein- Tyrosine Kinases
Ligand-induced receptor dimerization
Ligand binding activates the cytosolic kinase domain
Autophosphorylation of receptor
increases protein kinase activity
creates binding sites for other proteins that transmit signals downstream of the activated receptors

21. Receptor Protein- Tyrosine Kinases
SH2 domains mediate binding/activation of downstream signaling molecules
Signal propagates down to final target through kinase cascade

22. Receptor Protein- Tyrosine Kinases

23. Nonreceptor protein-tyrosine kinases
Similar RPTK, but the cytosolic domains have no catalytic activity
Cytokine receptor superfamily (interleukin-2 and erythropoietin)
Cytokine receptors function in association with non-receptor protein-tyrosine kinases
Example: Janus Protein-tyrosine kinases (JAK)
Cytokines regulate development and differentiation of lymphocytes during immune response

24. Non-receptor protein-tyrosine kinases
Ligand binding induces receptor dimerization
cross-phosphorylation of the associated nonreceptor protein-tyrosine kinases
Phosphorylation of receptor cytosolic domains
Formation of binding pocket for phosphorylation of other signaling proteins in the cascade