Cell Signaling Cell Signaling IISignaling molecules and their receptors

Cell BiologyCell BiologyLecture 12Lecture 12

Readings and ObjectivesReadings and Objectives• ReadingReading

– Russell Chapter 8 (not sufficient)

– Cooper: Chapter 15• TopicsTopicsLecture 12• Signaling Molecules and Their Receptors • Functions of Cell Surface ReceptorsLecture 13• Pathways of Intracellular Signal Transduction• Signal Transduction and the Cytoskeleton• Signaling Networks

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Cell SignalingCell SignalingIntroductionIntroduction• 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

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• 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

Signaling by secreted molecules

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Animation: Types of SignalingAnimation: Types of Signaling

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• 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

Signaling molecules

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• 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

1. Hydrophobic signaling molecules

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• 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

2. Neurotransmitters

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• Peptide hormones• Neuropeptides• polypeptide growth

factors– Short polypeptides,

one or more chains– Variety of functions

• All use cell membrane anchored receptors

3. Peptide signaling molecules

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• Eicosanoids: lipid signaling molecules which include prostaglandins, prostacyclin, thromboxanes, and leukotrienes

• Arachindonic derived from phospholipids, by phospholypase A2

4. Eicosanoids: lipid signaling molecules

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• Cyclooxygenases catalyse the conversion (targets for anti-inflammatory drugs)

• Short lived, thus act in autocrine or paracrine pathways• Platelet aggregation, inflammation, smooth muscle contraction

4. Peptide signaling molecules

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Two typesTwo 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.

Signaling Receptors

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Animation: Signal amplification Animation: Signal amplification

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Nuclear receptor superfamilyNuclear 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)

Intracellular receptors: Nuclear ReceptorsIntracellular receptors: Nuclear Receptors

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Thyroid hormoneThyroid 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

Intracellular receptors: Nuclear Receptors

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• 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

Membrane receptors: G-protein coupled receptrosMembrane receptors: G-protein coupled receptros

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• 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 alsoregulate ion channels

Membrane receptors: G-protein coupled receptrosMembrane receptors: G-protein coupled receptros

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Animation: G-protein coupled receptors

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• 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

Receptor Protein- Tyrosine Kinases

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• 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

Receptor Protein- Tyrosine Kinases

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• SH2 domains mediate binding/activation of downstream signaling molecules

• Signal propagates down to final target through kinase cascade

Receptor Protein- Tyrosine Kinases

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Receptor Protein- Tyrosine Kinases

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• 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

Nonreceptor protein-tyrosine kinases

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• 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

Non-receptor protein-tyrosine kinases

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