Lecture 10: Signal Transduction Flashcards
Transduction
-stepwise regulation of interactions of intracellular signaling proteins and often amplified
-info from environment transmitted inside a cell generates response
Eliciting of cellular response
-gene expression
-membrane transport
-metabolism
-cell growth/death
Transduction purpose
-coordinate cell metabolism, growth, development
-ensure homeostasis
-respond to external stimuli
Signal Transduction cascade
-sequential biochemical events to transfer a signal through a series of reactions that activate intermediate molecuels and to a final target
Signal cascade
- reception
- amplification
- G-protein
- Amplification
- Protein Kinase
- Amplification
7.Amplification
Signaling cascade amplification
by producing multiple intracellular activated molecules for every one receptor that is bound
Modes of cell-cell communication
-juxtacrine
-endocrine
-paracrine
-synaptic/neuronal
-autocrine
Juxtacrine signaling
-cell-cell contact
-2 surface proteins bind
Endocrine signaling
-hormones secretes into bloodstream
-LOW concentration
-HIGH affinity receptor
-response is minutes to hours
Paracrine signaling
-secreted ligands target nearby cells
-HIGH local concentration
-LOW affinity receptor
-rapid response (secs to mins)
Synaptic/neuronal signaling
-synapse between neuron and target is short distance
-VERY HIGH concentration
-VERY LOW affinity receptor
-dissociate rapidly
-technically specialized PARACRINE
Autocrine signaling
-sender and target are same cell
-response time similar to paracrine (secs to mins)
Secreted molecules
-first messengers
-ligands for receptors
-vary in size/chemical type
-receptors differ from intracellular proteins to integral membrane proteins
Big first messengers
-proteins
-polypeptides
Small first messengers
aa, lipids, nucleotides
Chemical types of first messengers
-steroids, vitamins, histamine, modified amino acids
Intracellular receptor for steroid/thyroid hormones, vitamins
-hydroPHOBIC first messenger
-Lipid-soluble hormone diffuses through plasma membrane and binds receptor
Signal Propogation of intracellular receptor of steroid hormones
-by changes in receptor upon binding
-leads to altered gene expression
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
- Protein phosphorylation
- 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
on
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
