Transcript Lecture 12

Cell Signaling I
Signaling molecules and their receptors
Cell Biology
Lecture 12
Readings and Objectives
• Reading
– 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
2
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
3
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
4
Animation: Types of Signaling
5
Signaling molecules
• Classes of signaling molecules
1. Hydrophobic signaling molecules
o
Use nuclear receptors
2. Neurotransmitters
3. Peptide signaling molecuels
4. Eicosanoids
– 2 through 4 use membrane receptors
6
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
7
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
8
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
9
4. Eicosanoids: lipid signaling molecules
• Eicosanoids: lipid signaling molecules which include prostaglandins,
prostacyclin, thromboxanes, and leukotrienes
• Arachindonic derived from phospholipids, by phospholypase A2
10
4. Peptide signaling molecules
• Cyclooxygenases catalyse the conversion (targets for antiinflammatory drugs)
• Short lived, thus act in autocrine or paracrine pathways
• Platelet aggregation, inflammation, smooth muscle contraction
11
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
12
remodeling, metabolic modulation, etc.
Animation: Signal amplification
13
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)
14
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
15
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
16
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
17
Animation: G-protein coupled receptors
18
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 proteintyrosine kinase activity
19
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
20
Receptor Protein- Tyrosine Kinases
• SH2 domains mediate binding/activation of downstream
signaling molecules
• Signal propagates down to final target through kinase
cascade
21
Receptor Protein- Tyrosine Kinases
22
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
23
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
24