Flashcards in SIGNAL transduction Deck (23):
What are the two major classes of hormones?
Group 1 hormones (steroids, iodothyronines, calcitriol, retinoids) bind their receptor in the cytoplasm, form a dimer, move into the nucleus and bind DRE. Group 2 hormones (polypeptides, proteins, glycoproteins, catecholamines) start their signaling through membrane receptors.
DRE (DNA hormone responsive elements)
What are the second messengers for group 2 hormones following receptor activation.
1) – cAMP
2) - cGMP-atrial naturetic factor, nitric oxide
3) calcium or phosphatydlinositol or both
4)-kinase or phosphate cascade
1 Alpha2 adrenergic catecholamines, beta-adrenergic catecholamines, ACTH, ADH (vasopressin), calcitonin, chorionic gonadotropin, corticotropin-releasing hormone, follicle-stimulating hormone, glucagon, lipotropin (LPH), luteinizing hormone, melanocyte-stimulating hormone, parathyroid hormone, thyroid-stimulating hormone (TSH).
3 acetylcholine (muscarinic), Alpha 1-adrenergic catecholamines, angiotensin II, antidiuretic hormone, cholecystokinin, gastrin, gonadotropin releasing hormone, oxytocin, platelet derived growth factor, substance P, thyrotropin releasing hormone.
4 adiponectin, chorionic somatomammotropin, epidermal growth factor, erythropoietin, fibroblast growth factor, growth hormone, insulin, insulin-growth factors 1 and 2, leptin, nerve growth factor, platelet-derived growth factor, prolactin
What are the hormones that act through cAMP?
The receptor for this group is the CGMPR family secretin like which uses various G proteins (Gas) to activate/deactivate adenylate cyclase as well as cause calcium release.
Alpha2 adrenergic catecholamines (Gi), beta-adrenergic catecholamines(Gq,i,s), ADH (vasopressin) > AVPR2, calcitonin>CALCR> (Gs,q), lipotropin (LPH), luteinizing hormone, melanocyte-stimulating hormone, parathyroid hormone(Gs), chorionic gonadotropin, ACTH, corticotropin-releasing hormone, follicle-stimulating hormone, glucagon, thyroid-stimulating hormone (TSH).
What are some hormones that act by affecting ion channels > increasing calcium levels, and/or activating phosphoinositide phospholipase C?
Ligands for rhodopsin like GPCR's release an alpha unit (Gaq11) which activates phospholipase C, which cleaves PIP2, releasing IP3 which opens calcium channels, and DAG, which attracts PKC to the cell membrane. Examples include:
acetylcholine (muscarinic), alpha 1-adrenergic catecholamines, angiotensin II, oxytocin, platelet derived growth factor (PDGF), substance P, antidiuretic hormone (ADH), cholecystokinin (>CCKAR and CCKBR), gastrin (>CCKBR), gonadotropin releasing hormone (GnRH > GnRHR), thyrotropin releasing hormone (TSH > TSHRH).
AVPR1A (arginine vasopressin receptor 1A)
CCKAR (cholecystokinin A receptor, CCK1, CCKA)
CCKBR (cholecystokinin B receptor, CCK2, CCKB, gastrin receptor, also responds to gastrin)
GnRHR (gonadotrophin releasing hormone receptor)
IP3 (inositol triphosphate)
NK1R (neurokinin 1 receptor)
PIP2 (phosphatidylinositol 4-5-biphosphate)
PLC (phospholipase C)
PKC (protein kinase C)
What are some hormones that act by stimulating a kinase or phosphate cascade?
adiponectin, chorionic somatomammotropin, epidermal growth factor, erythropoietin, fibroblast growth factor, growth hormone, insulin, insulin-growth factors 1 and 2, leptin, nerve growth factor, platelet-derived growth factor, prolactin
How do interleukin receptors work?
The extracellular components are immunoglobulin like and the intracellular end shares a TIR motif.
IL-1 receptors and TLR receptors then bind MYD88, TRAF3, TRAF6, IRAK resulting in the generation of transcription factors NF kB and AP1.
TIR (Toll IL-1 Receptor)
TRAF1 (TNF receptor-associated factor 1)
IRAK1 (interleukin-1 receptor-associated kinase 1)
AP-1 (activator protein 1), part of a heterodimeric protein which may include C-Fos, C Jun.
Are interleukin receptors specific for a single interleukin?
The same receptor responds to IL-1 and IL-18, another to either TLR5, TLR7, TLR9, and TLR11; separate ones for TLR2, TLR4, TLR3. Depending on the combination, NF-kB, AP1, IRF3, IRF7, may be generated.
How does the adiponectin receptor work?
This receptor is oriented with cytoplasmic N terminus, extracellular C terminus (opposite to G protein coupled receptors) and does not associate with G proteins. Activates AMPK and PPAR-a.
PPARa (peroxisome proliferator activated receptor alpha)
Name some promiscuous ligands and receptors.
Promiscuous ligands include:
acetylcholine (nAChR-nicotinic-ligand gated ion channel, mAChR, muscarinic, G protein coupled receptor, alpha unit deactivates adenylate cyclase, decreasing cAMP ), adrenergic stimulation activates 2 alpha receptors, and 3 beta receptors (all GPCR), arginine vasopressin receptors-3,
Promiscuous receptors include:
IL1R1 (interleukin 1 receptor 1 binds IL-1 alpha and beta, and IL1RA)
What peptide chains constitute the receptors for IL-1,2, and 5?
Interleukins 1, 2, and 5 rely on CD coreceptors.
IL-1 uses CD121a (IL1R1) along with IL1RaP (IL-1 accessory Protein) transmits signal. CD121b (IL1R2) is a decoy receptor that binds IL-1 alpha and beta but no signal results.
IL-2 uses CD25 (IL-2Ralpha), CD122 (IL-2Rbeta), CD132 (IL2Rgamma), and beta subunit CD131 (CSF2RB).
IL-5 receptor is CD125 (IL5RA) and beta subunit CD131 .
These receptors transmit a signal due to ability to bind JAK kinase which is activated by receptor aggregation after ligand binding.
IL1RA is the product of the gene IL1RN and is a decoy ligand.
CD131 (CSF2RB, granulocyte-macrophage colony-stimulating factor receptor, beta).
How are G protein coupled receptor classified?
GRAFS classification system for GPCR receptors is by ligand - Glutamate (22 genes), Rhodopsin like (662), Adhesion (33), Friizzled (11) / Taste2 (25), and Secretin (15).
Rhodopsin like receptors are a superfamily (evolutionarily linked but no longer share sequences) of 19 subtypes (639) + non catagorized types (23).
How are the main proteins responsible for signal transduction classified?
Cell signaling protein (types) are separated into Intercellular (4), cell surface(8), and intracellular (3). Calcium signaling, and lipid signaling involve all 3 varieties.
Intercellular-neuropeptides, growth factors, cytokines, hormones
cell surface protein receptors-ligand gated, enzyme linked, G protein coupled, immunoglobulin superfamily, integrens, neuropeptide, growth factor, cytokine
adapter proteins, GTP binding, map kinase,
calcium signaling-ion pumps, cell membrane calcium channels, adhesion molecules
lipid signaling - eicosanoids, lysophospholipids, steroids, others.
What are the main enzyme linked cell surface receptors?
Serine/threonine-specific protein kinase, receptor tyrosine kinase, guanylate cyclase
What are type I and type II cytokine receptors
Type I cytokine receptors respond to cytokines with four alpha helical strands. Receptors share common traducing chains namely:
1) gamma chain (CD130) IL-6 IL-11, IL-12, leukemia inhibitory factor, oncostatin M receptor.
2) common beta chain (CD131) GM-CSF receptor, IL-3, IL-5, and gp230
3) CD132; IL-2, IL-4, IL-7, IL-9, IL-13, IL-15,
Upon ligation these chains result in JAK kinase phosphorylation and signal transduction.
Type II cytokine receptors bind type I and type II interferons as well as IL-10, IL-20, and IL-22. They have variable immunoglobulin extracellular components and intracellular proline rich region that attract different Jak kinases. JAK1 and TYK2 for type 1 cytokines, and JAK1 and JAK2 for type 2 cytokines (IFN gamma).
What lipid products play a role in signaling?
Lipid products that play a role in signaling will include
1) phospholipase C phosphatidylinositol biphosphonate (PIP2),
2) G-protein coupled receptors: lysophosphatidic acid, sphingosine-1-phosphate, platelet activating factor (PAF), endocannabinoids, prostaglandins, retinol derivatives.
3)nuclear receptors: Steroid hormones, retinoic acid, prostaglandins.
What are the biogenic amines that target she protein coupled receptors?
Biogenic amines that target a G protein coupled receptor include
monoamines-histamine, serotonin, , catecholamine (norepinephrine, epinephrine, dopamine) and various trace amines.
How many types of enzyme linked surface receptors are there?
Enzyme linked surface receptors include
receptor protein serine/theonine kinase-3 types
Tyrosine kinase receptor families - 16+ types
Serine/theonine kinase receptors include bone morphogenic protein receptor 3, anti-Mullerian hormone receptor.
Tyrosine kinase receptor families including receptors for:
EGF, insulin receptor, PDGF receptor, FGF receptor, HGF (hepatic growth factor), TRK receptor, EPH (ephrin), LTK (leukocyte receptor tyrosine kinase), TIE (Angiopoietin), ROI (receptor tyrosine kinase-like orphan receptor), DDR (discoidin domain receptor), PTK7 (tyrosine-protein kinase-like 7), RYK (related to receptor tyrosine kinase), MuSK (muscle-specific kinase), ROS (proto-oncogene tyrosine-protein kinase), AATYK (apoptosis-associated tyrosine kinase), AXL (tyrosine-protein kinase receptor UFO) + unclassified.
What proteins are involved in producing NF-kB1 by stimulating the IL-1 receptor?
IL-1 stimulates the transmembrane receptor IL-1R, which has many associated proteins including IL-RAcP, MyD88, IRAK and TRAF6. MyD88, IRAK and TRAF6 also associate with Toll like receptors. These complexes stimulate NIK which then phosphorylates IkB-alpha (inhibitor of kappa B) which is then ubiquinated and destroyed releasing bound p65 (RelA) and NF-kB1 (p50) which work as a heterodimeric transcription factor for inflammatory response (~150) genes.
IL-RAcP IL-1 receptor accessory protein
MyD88 myeloid differentiation primary response gene 88
IRAK IL-1 receptor-activated protein kinase
TRAF tumor necrosis factor receptor-associated factor
NIK NF Kappa B-inducing kinase, MAP3K14
How does TGFbeta become an active ligand?
TGFbeta is a member of a superfamily which includes inhibins, activin, anti-mullerian hormone, bone morphogenic protein, and decapentaplegic. It is expressed by 3 genes in many cells and exists on the surface in a complex that is released through plasmin activation. Further enzymatic action is necessary to cleave the complexed ligand which dimerizes producing a 25 kDa active ligand.
What is the role of PKC in GPCR activation?
PKC is a serine/threonine kinase in 15 isoforms in different tissues which is stimulated by DAG to phosphorylate multiple substrates which then lead to smooth muscle contraction or other downstream effects.
PKC is active much longer than GTP remains bound to Ga subunit of the homotrimeric G protein.
PKC- protein kinase C
How does the TGF beta receptor work?
TGF beta receptor 2 (gene TGFBR2) binds TGF dimer, attracts TGF beta receptor 1 (TGFBR1) which activates serine/threonine kinase to phosphorylate R-SMAD leading to transcription factor activity. Endoglin is transmembrane glycoprotein that binds to TGFBR1,2,and 3 but not the ligand, and modifies downstream effects.
TGF transforming growth factor beta
R-SMAD receptor activated SMAD
endoglin CD105 important in angiogenisis, neoplasia
How many nuclear receptor ligand's are there?
9, CAR, FXR, LXR, PPAR, PXR, RAR, RXR, SHR, And TR.
CAR (Constitutive Androstane Receptor) recognized by endobiotic and xenobiotic substances.
FXR (farnesoid X receptor, NR1H4) responds to bile acids.
LXR (liver X receptor, regulates cholesterol, fatty acid, and glucose homeostasis)
PPAR (peroxisome proliferator-activated receptor, regulates cellular differentiation, development, and metabolism)
PXR (Pregnane X receptor, SXR, NR1I2, response to steroid and xenobiotic sensing)
RAR (retinoic acid receptor)
RXR (retinoid X receptor, heterodimerizes with CAR, FXR, LXR, PPAR, PXR, RAR, TR, and VDR)
SHR (steroid hormone receptor)
TR (thyroid hormone receptor)
The N terminal region determines transactional activity, the mid portion had DNA binding portion, then a hinge portion and the C terminal portion binds the ligand.