Flashcards in Test 2, 18. cell communication Deck (75):
What are the effects of cell signaling?
1. cytoskeletal changes
2. membrane changes
3. protein translation changes
4. cell cycle changes
What are the types of responses that external signals are able to produce?
1. Fast response
2. Slow response
What occurs for fast response in cell signaling?
1. changes in activity or the function of the enzyme or changes of proteins in the cell
What occurs for slow response in cell signaling?
1. proteins change in amounts by changing the expression of genes
What is endocrine signaling?
1. used for long distance signaling
2. signal into bloodstream into target cell
3. long lasting in order to allow transport through the circulatory system
What is paracrine signaling?
1. local action, not freely diffusable
2. short lived signal such as NT
What is autocrine signaling?
1. cell responds to a signal that it secreted itself
2. growth factor in cancer cells
What effects can acetylcholine have on different cells?
1. acts on heart muscle cells to relax them
2. skeletal muscle cells will contract
3. salivary gland cells cause secretion of saliva
What are the different proteins that can be activated via signal transduction?
1. activation of metabolic enzymes that alter metabolism
2. activation of gene regulatory proteins that alter gene expression
3. activation of cytoskeletal proteins that alter cell shape or cause movement
What are the signaling cascade components?
1. signals: secreted by exocytosis, signals can stay near or go far
2. receptors: bind specific signal molecules with high affinity (signals are then produced in low levels)
3. effectors: alter activity of many different proteins and generate second messengers from targeted receptors inside the cell
What are the lypophilic hormone classes?
What are the steroid hormones?
progesterone, estradiol, testosterone, cortisol, aldosterone, vitamin D
What are the thyroid hormones?
What are the retinoid hormones?
retinol, retinoic acid
What are the hydrophilic hormone classes?
1. amino acid derivatives
2. lipid metabolism
What are the hormones in the amino acid derivatives?
histamine, serotonin, melatonin, dopamine, norepinephrine, epinephrine
What are the hormones from lipid metabolism?
What are the hormones derived from polypeptides?
insulin, glucagon, cytokines, thyroid-stimulating hormone
What are the two types of signaling receptors?
1. intracellular: have receptor in the cytosol that alter gene expression in nucleus (estrogen)
2. cell surface: have external, transmembrane, cytosolic domain that generate a signal via conformational changes.
What molecules bind with intracellular receptors?
1. small hydrophobic
2. some lypophilic hormones
What are the majority of signaling molecules?
1. cell-surface and hydrophilic
What are the three main types of cell signaling receptors that are located in the cell membrane?
1. ion-channel coupled receptors
2. G-protein coupled receptors (GPCR)
3. enzyme coupled receptors (RTK)
Which signaling receptor is the major target for the majority of drugs?
The GPCR binds with the g protein in the cytosol that has what characteristics?
1. guanine nucleotide binding proteins with alpha, beta, gamma subunits
What is the function of G protein being activated by GPCR?
1. regulate target enzymes
2. but there is no intrinsic catalytic activity
What is the pathway of GPCR?
1. ligand binding
2. GPCR activates trimeric G protein
3. activate effector enzyme
4. activate 2nd messenger
5. 2nd messenger targets become active
6. cause biological response
What are common hydrophobic (lipophilic) ligands and signals?
5. retinoic acid
6. Vit D3
What domains are found on the intracellular receptors?
1. transcription activating
4. COOH, which binds to inhibitory proteins
Is GTP-alpha and active kinase?
1. no, while it may be active, it will not transfer phosphates. It causes a conformational change that leads to signal production
What is the function of Guanine Nucleotide Exchange Factor (GEF)?
1. phosphorylates inactive GDP-alpha to active GTP-alpha
What is the function of GTPase activating Protein (GAP)?
1. removes phosphate from the GTP-alpha active unit.
2. Returns the active unit to an inactive GDP-alpha unit
What are the steps of G-protein relaying signals?
1. ligand binds receptor
2. receptor undergoes conformational changes
3. receptor binds to G protein, then acts as GEF
4. Galpha, changes conformation to remove GDP and bind GTP
5.G-alpha binds with effector molecule
6. effect is generated.
In most cases what is the effector molecule that active G-alpha binds with?
1. adenylyl cyclase, which leads to production of cAMP.
What is required for ATP to generate cAMP?
1. adenylyl cyclase
What is required for cAMP to generate 5'-AMP?
cyclic AMP phosphodiesterase.
- has become large target of drugs as it is able to control activation/inhibition of signals to produce certain effects
Do RTK use cAMP for signaling?
1. not at all
Protein Kinase A (PKA) is dependent on what molecule, that in it's presence will allow PKA to become active and phosphorylate other proteins?
1. dependent on level of cAMP.
2. require 4 cAMP to release two subunits of active PKA
How is PKA able to regulate protein activity?
1. PKA adds two negatively charged phosphates that will alter the CONFORMATION of the target protein
What are four effects of PKA acting on target proteins?
1. form new structure specifically requiring phosphate addition
2. control activity of enzymatic target proteins
3. alter localization of target proteins
4. alter abundance of target proteins
If amplification of signals has something wrong occur it can be problematic. How is this the case with cholera?
1. activation signal is turned on, which leads to rapid ejection of Cl from cells. This leads to ejection of water as well, causing rapid dehydration of the body and sometimes death
What does the cholera toxin do specifically to signaling processes?
1. G-alpha is kept in active GTP bound form leading to overproduction of cAMP
2. cAMP acts on effector and causes rapid loss of water and Cl ions
ability to turn off or reject the signal
What is one method to decrease PKA activity?
1. decrease hormone levels--> decreases adnylyl cyclase activity--> decreases cAMP
What does it mean if a receptor is sequestered?
1. receptor is internalized and stored in an endosome until the signal causing this effect is removed
How are receptors destroyed?
1. receptor is internalized into endosome and fused with lysosome, forming endolysosome which will then degrade the proteins
What is the function of G protein receptor kinases (GRK)?
1. phosporylate receptor to allow arrestins to bind intracellularly
2. bind to 3rd lood of G-alpha, preventing interactions
What can the process of using arrestins on GPCR be classified as?
What specific protein is responsible for activating adenylyl cyclase?
What specific protein is able to inhibit adenylyl cyclase?
What is the effect of Gq-alpha-GDP being activated to the GTP form?
1. Adenylyl cyclase is not activated
2. Phospholipase C is activated.
Active Phospholipase C (PLC) is able to activate what signaling cascade?
1. cleaves PIP2 to form DAG, and IP3
2. IP3 will release Ca from the ER, by binding to IP3-gated Ca channels. Ca can then activate Ca-calmodulin dependent proteins
3. DAG will activate Protein kinase C which can phosphorylate a variety of substrates
What does PKC require in order to become active and phosphorylate other substrates, in order to continue the signaling cascade?
1. combination of DAG and Ca
Enzyme-coupled receptors all create docking site for other proteins. What are three examples of signaling receptors utilizing this method?
1. tyrosine kinase
2. JAK-STAT receptors
3. serine/threonine kinases
What happens when a ligand binds to an inactive receptor tyrosine kinase?
1. conformational change occurs to form a dimer
2. the kinase domain then undergoes autophosphorylation
What are RTK most likely to be activated by?
1. growth factors: which promote cell growth
What are the different growth factors that can activate RTK?
1. epidermal (EGF)
2. platelet derived (PDGF)
3. fibroblast (FGF)
4. Insulin-like (IGF-1)
5. nerve (NGF)
* growth factors were named where they were discovered but are found in multiple cell types
Autophosphorylation of RTK allows for specific proteins, Not G proteins, to bind to the scaffold structure intracellularly. What proteins bind to the phosphorylated RTK enzymatic tails?
1. proteins with SH2 domains bind to phospotyrosine
2. in mammals SH2=Grb2
SH2 is homologous with Src. Src is an oncogene, and therefore it can be assumed that SH2 is also an oncogene.
True, mutation could lead to continuous activation of growth factors, and cause uncontrolled cell growth or tumor growth.
What is the complex that binds to the enzymatic tails of RTK?
1. SH2 domain of Grb2
2. which binds the SH3 domain of SOS
3. SOS binds to Ras-GDP
What is the major role of SOS in terms of RTK activation?
1. ligand binding leads to SOS causing conformational change in RAS to remove GDP and allow binding of GTP in order to propagate the signal downstream
What will Sh3 domain of Grb2 bind to on SOS?
What is Ras?
1. first human oncogene discovered
2. crucial role in cell division and frequently mutated in cancer.
Activation of RTK causes activation of what downstream signaling factors?
3. MAP kinase kinase (Mek)
4. MAP kinase (Erk)
5.changes in protein activity and gene expression
What signaling mechanisms can insulin use with RTK pathways?
1. RAS-dependent pathway
2. RAS-independent pathway
What proteins are used in RAS-dependent insulin signaling?
1. IRS-1 as scaffold, which is phosporylated
2. Grb2 which activates RAS system
3. MAPkinase pathway
4. protein phosphorylated
What are the effects of using the RAS-dependent pathway of insulin formation?
1. alteration to gene transcription
2. produces increased glucose uptake (more insulin produced) and glycogen synthesis
What are the proteins used for RAS-independent pathway of insulin signaling?
1. IRS-1 forms phosphorylated scaffold
2. PI-3 kinase binds and activates PKB
3. PKB will activate the proper proteins
What is the effect of using RAS-indepedent pathways of insulin signaling?
1. increased glucose uptake and glycogen synthesis by cells
2. increased GLUT4 to PM, and activate glycogen synthase
In short what is the quick, down and dirty pathway of RTK signaling pathway?
1. growth factor binds receptor
2. receptor is now active tyrosine kinase
3. autophosphorylates nearby structures
4. Bind Grb2-SOS-Ras-Raf
5. MAPkinase pathway produces gene transcription
6. signaling molecules are proto-oncogenes that can easily mutate to oncogenes.
How do JAK-STAT receptors differ from the RTK receptors?
1. they still form dimers
2. much simpler form of signaling pathway.
What is the signaling pathway of JAK-STAT receptors?
1. ligand binds, causing receptor dimerization and JAK bind
2. JAK phosphorylate one another
3. phosphorylated receptor binds STATs
4. STATs dissociate and migrate to the nucleus to bind to proper DNA region
Which type of receptor has the most simple form of signal pathway?
1. serine/threonine receptors and Smad