Signal-Transduction Pathways Flashcards
*Understand what a signal transduction cascade is and what second messengers do.
signal transduction cascade- chain of events that convey signal through the cell.
Cascade components:
1. release of PRIMARY MESSAGE as response to physiological circumstance
2. reception of primary message by a RECEPTOR (usually integral membrane protein)
3. relay of the detection of primary message to cell interior, by generating INTRACELLULAR SECOND MESSENGER (like cyclic AMP, GMP, IP3, Calcium, DAG)
4. ACTIVATION of EFFECTOR molecules by second messenger that result in physical response
5. termination of signal cascade
purpose of secondary messengers: relay signals sent by cell surface receptors to effector molecules.
(sum up signal > reception to transduction to response
*Be able to describe the three major classes of membrane receptors.
Three major classes of membrane receptors:
- seven transmembrane receptors associated with heterotrimeric G proteins
- dimeric membrane receptors that RECRUIT protein kinases
- Dimeric protein receptors that ARE protein kinases.
*understand the mechanism of the β-adrenergic receptor as an example of a 7 -
transmembrane-helix (7TM) receptor (G-protein coupled receptor (GPCR)).
- The Beta-adrenergic receptor is activated by binding EPINEPHRINE (adrenaline).
- After binding of epinephrine, the cytoplasmic aspect of Beta adrenergic receptor activates a HETEROTRIMERIC G-protein (contains, alpha subunit, beta gamma dimer).
- upon activation by receptor, alpha subunit dissociate from Beta gamma dimer and exchanges GDP for GTP.
- The GTP bound ALPHA subunit transmits the signal to other cellular components. (since 7TM receptors are always associated with G proteins, they are often called G PROTEIN COUPLED RECEPTORs (GCPRS).
- in the beta adrenergic signal transduction pathway, the activated G protein, G-alphas, stimulates the integral membrane enzyme, ADENYLATE CYCLASE
- activation of adenylate cyclase leads to synthesis of secondary messenger cyclic Adenosine Monophosphate (cAMP)
*Be able to describe the phosphoinositide cascade.
The phosphoinositide pathway involves G- alpha q protein as a component of trimeric G protein complex.
- G alpha- q activates PHOSPHOLIPASE C, which cleaves the membrane LIPID PHOSPHATIDYLINOSITOL BISPHOSPHATE in two second messengers; inositol 1, 4 5-triphosphate (IP3) and Diacylglycerol (DAG).
- IP3 binds to IP3-gated channel (IP3 receptor) in the endoplasmic reticulum, allowing the influx of Calcium ions into the cytoplasm. The Calcium ions regulate a host of cellular functions.
- DAG, along with Calcium, activate Proteins kinase C (serine/threonine kinase).
*Understand how growth hormone works in terms of the receptor tyrosine kinase
some growth factors and hormone receptors like EPIDERMAL GROWTH FACTOR and INSULIN bind to receptors that are tyrosine kinases called receptor tyrosine kinases (RTK).
upon growth factor or hormone binding, the receptors form dimers.
receptor dimerization leads to cross-phosphorylation and activation of two intracellular kinase domains.
The phosphorylated kinases form docking platforms for other components of signal transduction pathway.
mutations in these receptors for humans cause variety of pathologies.
*Be familiar with insulin signaling and how the pathway works.
Insulin consists of two polypeptide chains linked by disulfide bonds.
insulin receptor- RECEPTOR TYROSINE KINASE.
1. upon insulin binding to receptor, the receptor dimers form.
2, dimerization leads to cross phosphorylation and activation of kinase domains
3. activated kinases of insulin receptor phosphorylate insulin-receptor substrates (IRSs). the phosphorylated IRSs are adaptor proteins to convey insulin signal
4. phosphoinositide- 3 kinase binds IRS and then phosphorylates phosphatidylinositol 4, 5, bisphosphate (PIP2) to form phosphatidyinoitol 3, 4, 5 triphosphate (PIP3).
5. PIP3 activates PIP3 dependent kinase, which phosphorylates and activates kinase AKT
6. AKT phosphorylates glucose transporter (GLUT4), increasing glucose uptake by cells, and enzymes that convert glucose into glycogen.
*Understand the role of the calcium ion and how CaM (calmodulin) kinase and Ca2+ - ATPase
pump work. what is another pathway, that Calcium plays a role in?
calcium is an important second messenger in eukaryotic signal transduction pathways.
The protein Calmodulin (CaM) is a common Calcium sensor found in cytoplasm of all cells.
Calmodulin, with four calcium binding sites called EF hands, is activated upon binding Calcium.
the Ca^2+-Calmodulin complex activates a variety of biochemical targets, including pumps such as PM Ca^2+ ATPase and Calmodulin-dependent protein kinase (CaM kinase)
CaM kinase regulates metabolism of fuel, neurotransmitter synthesis and release
Calcium-CaM complex stimulates Calcium ATPase which helps terminate calcium signal
recall, Calcium also plays role in phosphoinositide pathway.
What is the role of seven transmembrane helix (7TM ) receptors? How does it respond to ligand binding?
7TM helix receptors mediate a host of biological functions by responding to a variety of signal molecules (ligands) including hormones, tastants, and photons.
The binding of ligand outside cell induces a structural change in the receptor that can be detected inside the cell.
What is the composition of an un-activated G-protein?
Heterotrimer consisting of alpha subunit bound to GDP , and Beta and gamma subunits.
what is the integral membrane enzyme that is stimulated by G-alpha s? What does this enzyme further synthesize.
Adenylate cyclase
stimulation of the cyclase synthesizes cyclic amp (cAMP)
What occurs after cyclic AMP has been synthesized? What does it activate and how?
cyclic AMP activates protein Kinase A (PKA).
Protein kinase A consists of two pairs of subunits; 2 catalytic (C) subunits and 2 Regulatory (R) subunits.
binding of cAMP by the regulatory subunits dissociates these same subunits from the complex, resulting in the activation of 2 C subunits.
the activated C subunits continue the epinephrine signal transduction by phosphorylating protein targets that alter physiological functions of the cell.
Explain what Cushing syndrome is and how it it involves the protein kinase.
Cushing syndrome- collection of diseases resulting from excess cortisol secretion by adrenal cortex.
symptoms: muscle weakness, thinning skin, osteoporosis
Cortisol - steroid hormone that has effect of stimulating glucose synthesis, suppressing the immune response and inhibiting bone growth.
mutation in protein kinase A that makes it very active, can result in the syndrome, as catalytic subunit is altered to point where it no longer binds to regulatory subunit. Even in absence of cAMP, Kinase A will always be active (unregulated secretion).
How can the epinephrine-initiated pathway be shut down (leading to reset of G proteins)?
Can be shutdown by:
1. G alpha has inherent GTPASE ACTIVITY that cleaves bound GTP to GDP. THe G alpha bound to to GDP will then spontaneously reassociate with beta-gamma subunits and terminate activity of G protein.
2. cyclic AMP phosphodiesterase coverts cAMP to AMP, which cannot activate protein kinase A
3 Epinephrine-Beta adrenergic receptor interaction is reversible. Once the concentration of epinephrine falls, the receptor will no longer be active.
What are two major compounds besides epinephrine that activate 7TM (seven trans-membrane) helix?
growth factors and Vasopressin activates 7TM.
Describe the human growth receptor and how it reacts with hormone binding.
Human growth hormone receptor- monomeric integral membrane protein with an extracellular and intracellular domain joined by intramembrane alpha-helix.
- upon hormone binding, receptor dimerizes
- Dimerization of extracellular domains of receptor. brings together the intracellular domains, which are associated with JANUS KINASE 2 (JAK2)
- Each JAK phosphorylates its partner on tyrosine residue, activating the two kinases.
- activated kinases then phosphorylate other targets, including regulator or gene expression called SIGNAL TRANSDUCER and SIGNAL ACTIVATOR OF TRANSCRIPTION 5 (STAT5).
- STAT 5 further propagates signal by altering gene expression
