1. reception 2. amplification 3. G-protein 4. Amplification 5. Protein Kinase 6. Amplification 7.Amplification

Lecture 10: Signal Transduction Flashcards by Brooke Thornburg

Transduction

-stepwise regulation of interactions of intracellular signaling proteins and often amplified
-info from environment transmitted inside a cell generates response

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Eliciting of cellular response

-gene expression
-membrane transport
-metabolism
-cell growth/death

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Transduction purpose

-coordinate cell metabolism, growth, development
-ensure homeostasis
-respond to external stimuli

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Signal Transduction cascade

-sequential biochemical events to transfer a signal through a series of reactions that activate intermediate molecuels and to a final target

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Signal cascade

reception
amplification
G-protein
Amplification
Protein Kinase
Amplification
7.Amplification

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Signaling cascade amplification

by producing multiple intracellular activated molecules for every one receptor that is bound

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Modes of cell-cell communication

-juxtacrine
-endocrine
-paracrine
-synaptic/neuronal
-autocrine

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Juxtacrine signaling

-cell-cell contact
-2 surface proteins bind

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Endocrine signaling

-hormones secretes into bloodstream
-LOW concentration
-HIGH affinity receptor
-response is minutes to hours

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Paracrine signaling

-secreted ligands target nearby cells
-HIGH local concentration
-LOW affinity receptor
-rapid response (secs to mins)

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Synaptic/neuronal signaling

-synapse between neuron and target is short distance
-VERY HIGH concentration
-VERY LOW affinity receptor
-dissociate rapidly
-technically specialized PARACRINE

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Autocrine signaling

-sender and target are same cell
-response time similar to paracrine (secs to mins)

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Secreted molecules

-first messengers
-ligands for receptors
-vary in size/chemical type
-receptors differ from intracellular proteins to integral membrane proteins

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Big first messengers

-proteins
-polypeptides

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Small first messengers

aa, lipids, nucleotides

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Chemical types of first messengers

-steroids, vitamins, histamine, modified amino acids

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Intracellular receptor for steroid/thyroid hormones, vitamins

-hydroPHOBIC first messenger
-Lipid-soluble hormone diffuses through plasma membrane and binds receptor

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Signal Propogation of intracellular receptor of steroid hormones

-by changes in receptor upon binding
-leads to altered gene expression

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Steroid Nuclear Receptors

-initiate signaling processes activated by steroid hormones
-changes in gene expression over HOURs to DAYs
-bind hormone then bind to specific sites on DNA to activate transcription
-cancer

Steroid Nuclear Receptors as TFs

-direct interaction with DNA and control gene expression
-key to embryonic development, and homeostasis, metabolism

HETEROdimer Nuclear Receptor

-Retinoid X receptor and liver receptor bound to DNA in response element
-DBD-hinge-LBD
-2 DBDs bind DNA promoter regions
-LBD has agonist ligands and peptide from NR coactivator

Nuclear receptors as drug target

-ligand inducible transduction
-drugs blocking estrogen or androgen receptor in breast and prostate cancers

Thyroid Nuclear Receptor

-thyroid hormone
-lipid soluble
-diffuse through membrane
-binds receptor inside cell
-HOMOdimerization of receptor
-recruitment of coregulatory proteins
-promotes DNA binding and specific recognition of TRE
-turns on or off transcription

-green DBD on top
-purpkle LBD on bottom
-ligand bind middle of LDB

TNR resembles heterodimer nr

Integral membrane protein

-effector protein -coupling protein = activate effeector and other enzymes -enzyme activity =alters receptor activity -opens ion channel =changes membrane potential

Second messengers

-sometimes -small -transmit and amplify initial signal from extracellular first messenger binding to receptor -inorganic or organic products of enzyme-catalyzed reactions

Second messenger ex

-ions: Ca+ -water-soluble: cAMP, cGMP, IP3 -lipid soluble: DAG, PIP3

Downstream signaling controls

1. Protein phosphorylation 2. GTP-binding Regulatory Proteins

Phosphorylation

-mods that control protein-protein interactions and enzymatic activity -induce conformational change to in/decrease enzyme activity -promote/disrupt interaction

Phosphorylation by Protein Kinase + ATP

-activates enzyme

phosphatase

inactivates enzyme

Tyr, Ser, Thr

protein phosphorylated on either

Promotion of protein interaction via phosphorylation

-binding site with phosphorylated residue is recognized by binding partner -unphosphorylated one is not

Disruption of protein interaction via phosphorylation

vice versa

Recognitionylation

Recognition

Phospho-Y and phospholipid

-large assmebly of proteins from under control of phosphorylation

GTP-binding regulatory proteins

-exchange of

G proteins (GTPases)

-bind and hydrolyze GTP to GDP -off/on switch

GDP bound

off

GTP bound

GTP hydrolysis

turns off signal =GDP

Guanine nucleotide exchange factors (GEFs)

-catalyze exchange of GDP for GTP -binds GDP complex to promote GDP release followed by binding of GTP -ACTIVATES G-protein

Cellular Response maximal limit

-at lower ligand concentration -shows amplification without need for ligand engaging all cellular receptors

Turn off cellsurface receptors = turn off signaling

-reduce level of message or agonist availability in extracellular vicinity of targert cell -receptor loss/desensitization

Reducing availability

-common in synaptic signaling -rapid re-uptake of neurotransmitters by transporters -serotonin, dopamine, SERT -breakdown by enzymes

Receptor loss/desensitization

-reduced receptor availability by internalization and sometimes degradation -functionally adapted by modifying receptors (de/phosphorylation) to be less active