Unit 3: Chapter 13 Flashcards
Signal transduction cascade commonalities:
- release of primary messenger due to physiological circumstance
- receptor receives primary messenger
- relay of primary messenger to inside cell by intracellular second messenger
- activation of effector molecules by second messenger to result in physiological response
- Termination of signal cascade
Since signal transduction is on, it needs to …
turn off
How does cancer cells indicate something wrong with signal transduction?
Cancer cells is uncontrolled cell division and indicates signal transduction is always on
Signaling molecules
Primary messenger aka ligand
Produced by signaling cells and bind to receptor on or in target cell
After signal molecule binds to receptor what happens
Receptor changes conformation
What are the two types of receptors?
- Cell surface receptors
- Intracellular receptors
Location of receptor depends on what
Whether signaling molecule is polar or nonpolar
Cell Surface receptors
- Integral membrane receptors (transmembrane)
- Bind to signaling molecules on extracellular domain of receptor of target cell membrane
- Signal does not need to cross membrane
Intracellular receptors
Nonpolar signaling molecules can cross target cell membrane and bind to receptor in cytosol or nucleus
Target cells detect signal using what
Receptor protein
Second messengers
Relay info from receptor signal molecule complex and amplify signals inside the cell
What determines whether a cell responds to a signaling molecule?
Presence of receptor proteins of target cell
3 Major classes of cell surface receptors
- Seven transmembrane helix receptors (G-Protein coupled receptors aka GPCRs) associated with heterotrimeric G proteins
- Dimeric membrane receptors that recruit tyrosine kinase
- Dimeric protein receptors that are protein tyrosine kinase
Kinase
enzyme that transfers phosphate group ATP to target molecule (catalyze phosphorylation)
Phosphatase
enzyme that catalyzes dephosphorylation
GTPase
enzyme catalyzes hydrolysis of GTP to GDP and inorganic phosphate
Cyclic AMP phosphodiesterase
continuously converts cAMP to AMP
GPCR: G Protein Coupled Receptors
- 7 membrane
- Mediate a host of biological functions by responding to a variety of signal molecules aka ligands
- Binding of ligand occurs outside the cell induces receptor change conformation which is detected inside the cell
- attractive target for development of drugs
Activation of protein kinase A by G Protein pathway
- Beta adrenergic receptor (type of GPCR) binds to epinephrine (first messenger) which changes conformation that is detected inside the cell by the G protein
- Trimeric G protein is the partner in the coupled rxn
- When signal is off G protein has GDP and is trimeric
- When signal is on G protein changes conformation and how has GTP and disassociates to alpha subunit
- Next target is adenylate cyclase (transmembrane embedded integral protein)
- Adenylate cyclase activates cyclic AMP (second messenger) which activates protein Kinase A
- Protein Kinase A will add phosphate to more target cells
In epinephrine signal transduction pathway, upon activation to receptor
alpha subunit dissociates by beta gamma dimer and exchange GDP to GTP
How do G proteins reset?
Reset themselves through GTP Hydrolysis
GTP + H20 –> GDP + Pi
G protein to be inactive
How to shut down epinephrine initiated pathway
- G alpha protein binds to GDP to reassociate with beta gamma units terminate activity of G protein
- Cyclic AMP phosphodiesterase converts cAMP to AMP so protein kinase not activated
- Epinephrine beta adrenergic receptor interaction is reversal, no signal binding to receptor does not initiate signal pathway
How to reset GTP alpha subunit?
GTP alpha subunit hydrolyzes to GDP and reassociates with beta gamma subunits for signal to turn off
Phosphoinositide pathway to generate IP3 and DAG
- G protein coupled receptors activate phosphoinositide pathway generating IP3, DAG, Ca2+
- G alpha protein activates phospholipase C which cleaves membrane lipid PIP2 into 2 second messengers: IP3 and DAG
- Diaglycerol (DAG) never diffuses and stay in membrane
- IP3 diffuses into cytoplasm and bind to IP3 gated channel (receptor) in ER which allows for calcium channels top open
- DAG and Ca2+ activate protein kinase C
Receptor dimerization may result in
Tyrosine kinase recruitment
Human growth hormone receptor
Monomeric integral membrane protein with an extracellular and intracellular domain joined intramembrane alpha helix
When does receptor dimerize
Upon hormone binding to receptor
Which signal transduction pathways use G Protein Coupled Receptors?
Activation of Protein kinase A with epinephrine
IP3 and DAG Pathway
Which signal transduction pathways use receptor Tyrosine Kinase?
JAK2 and STATS pathway
EGF Signaling
Insulin Signaling
Receptor Tyrosine Kinase activates JAK2/ STAT5 Pathway
- Dimerizatrion of extracellular domains of receptor brings together intracellular domains associated with JAKS2
- Each JAK phosphorylates its partners (cross phosphorylat ion) on a tyrosine residue to activate 2 kinases
- ## Activated kinases phosphorylate targets including STAT5
STAT5
Regulator of gene expression and further propagates the signal
EGF Signaling Pathway Through Receptor Tyrosine Kinase
- EGF Signaling binds to EGF receptor for dimerization to occur and cross phosphorylation by tyrosine kinase
- Tyrosine Kinase adds phosphate to tyrosine
- Grb-2 protein is activated
- SOS connects GP2 and GDP and stimulate exchange GDP for GTP in Ras protein
- Ras protein becomes active with GTP
- Last protein go downstream to activate more cells
If Ras protein has GDP, it is
Inactive
SOS
Adaptor protein connecting signals togehter of Grb-2 and GDP
Stimulates exchange GDP for GTP in Ras protein
If Ras protein has GTP, it is
Active
Ras protein
Monomeric G protein (Single polypeptide chain)
intrinsic
has GTPase activity which controls signal duration
Regulates cell growth through serine or threonine protein kinases
Rho (subfamily of Ras)
reoorganizes cytoskeleton through serine or threonine protein kinases
Rab (subfamily of Ras)
plays a key role in secretory and endocytotic pathways
Insulin signaling pathway through receptor tyrosine kinase
- Insulin receptor tyrosine kinase is ALREADY DIMER (even in absence of insulin)
- Insulin binding causes change in structure which results in cross phosphorylation by 2 kinase domains
- activated kinase of insulin receptor phosphorylates IRSs
- phosphorylated IRSs covey insulin signal
- phosphoinositide 3- kinase binds to IRS and phosphorylates PIP2 to PIP3
- PIP3 activates PIP3 dependent protein kinase (PDK1)
- PDK1 phosphorylates and activates kinase Akt by ATP to ADP
- Akt phosphorylates enzymes that control GLUT4, increasing glucose uptake, and convert glucose into glycogen
Insulin
Hormone protein that is secreted when blood is rich in glucose
Biochemical signal for fed state
A receptor tyrosine kinase
Consists of 2 polypeptide chaisn linked by disulfide bonds
Which pathway is the receptor already a dimer?
Insulin signaling pathway
