Chapter 6. Signal Transduction (signaling)
Recommended Article : 【Biology】 Biology Table of Contents
1. Overview
2. Transduction
3. Receptor 1. G Protein-Coupled Receptors
4. Receptor 2. Tyrosine Kinase Receptors
5. Receptor 3. Serine/Threonine Kinase Receptors
6. Receptor 4. Intracellular Receptors
7. Receptor 5. Ion Channel Receptors
8. Receptor 6. Adhesion Receptors
9. Receptor 7. Other Receptors
10. Signal Transduction Enhancers
11. Signal Transduction Inhibitors
a. Cell Fate
1. Overview
⑴ Life activities are composed of around 200-300 core biological pathways.
⑵ Process
① Step 1. Reception
② Step 2. Transduction : Signal amplification through phosphorylation cascade is a representative process.
③ Step 3. Response : Reactions in the nucleus are related to genes, while reactions in the cytoplasm are related to proteins.
⑶ Characteristics
① Specificity : Ligand specificity
② Integration
③ Amplification : Reaction amplification
④ Sensitivity attenuation / Adaptation
⑤ Communication
⑷ Epistasis
① Epistasis in signal transduction : The signal that acts last is considered to have higher epistasis.
② Epistasis in genetics : The gene that acts first is considered to have higher epistasis.
2. Transduction
⑴ Overview
① Case 1. When the signal attaches to Ser or Thr of a signaling protein : Possible due to the presence of -OH group.
○ Src
○ FAK
○ JAK
○ PTP
○ STP
② Case 2. When the signal attaches to Tyr of a signaling protein : Possible due to the presence of -OH group.
○ Case 1 and Case 2 do not occur simultaneously.
③ Case 3. CheA
○ Histidine kinase
○ Not involved in serine/threonine pathways.
⑵ Type 1. MAPK (Mitogen-Activated Protein Kinases)
① Overview
○ Common principle : MAPKKK → MAPKK → MAPK
○ Located near the nucleus
② 1-1. ERK1/2 (Extracellular Signal-Regulated Kinase) Module : Mammalian MAPK cascade
○ 1st. Growth factors, mitogens
○ 2nd. MAPKKK stage : A-Raf, B-Raf, C-Raf
○ 3rd. MAPKK stage : MKK1/2
○ 4th. MAPK stage : ERK1 (MAPK3), ERK2 (MAPK1)
○ 5th. Proliferation, differentiation, division
③ 1-2. JNK (c-Jun N-terminal kinase) / p38 Module: Mammalian MAPK cascade
○ 1st. Stress stimuli
○ 2nd. MAPKKK stage : MEKK1/4, ASK1/2, MLK1/2/3
○ 3rd. MAPKK stage : MKK3/6, MKK4, MKK7
○ 4th. MAPK stage : p38α/β/γ/δ, JNK1/2/3
○ 5th. Cellular apoptosis, inflammatory response, cell differentiation, cell cycle arrest
④ 1-3. ERK5 Module : Mammalian MAPK cascade
○ 1st. Morphological stimuli
○ 2nd. MAPKKK stage : MEKK2/3
○ 3rd. MAPKK stage : MKK5
○ 4th. MAPK stage : ERK5
○ 5th. Formation of epithelial cell lumen
⑤ 1-4. Yeast MAPK cascade
○ α-factor pheromone → Ste11 → Ste7 → Fus3 → Cell cycle arrest, mating
○ Starvation → Ste11 → Ste7 → Kss1 → Filament elongation
○ Osmolarity → Ssk2/22 → Pbs2 → Hog1 → Glycerol synthesis
○ Storage → Bck1 → MKK1/2 → Mpk1 → Cell wall remodeling
○ Nutrient depletion → Cak1 → Smk1 → Ascus division, sporulation
⑶ Type 2. CDK (Cyclin-Dependent Kinase)
① Function : Regulation of cell cycle
② Types and regulators
○ Cyclin A, B, D, E
○ CDK 1, 2, 4, 6
○ MPF, CDC, CDI, APC
○ Myc
○ p53, p21, mdm
○ Bax, cytochrome C, Caspase
○ Rb, E2F
○ WEE1, CDC25
⑷ Type 3. NF-κB pathway
① 1st. NF-κB forms a complex with Iκ-B protein in the cytoplasm under normal conditions.
○ Iκ-B inhibits the movement of NF-κB to the nucleus.
② 2nd. Signal molecules like TNF-α trimer bind to receptors.
③ 3rd. IKK (inhibitor kappa kinase) is activated.
④ 4th. Serine-threonine kinase RIP is activated.
⑤ 5th. Iκ-B is activated and degraded in the cytoplasm.
⑥ 6th. NF-κB is dissociated from Iκ-B and moves to the nucleus.
⑦ 7th. NF-κB produces proteins related to macrophage inflammation.
○ Macrophages have pro-inflammatory M1 and anti-inflammatory M2 types.
○ NF-κB helps macrophages transition to the M1 type.
⑸ Type 4. mTOR (Mammalian Target of Rapamycin)
① Serine/threonine kinases evolutionarily conserved from yeast.
② Inhibited by rapamycin.
③ PI3K → Akt → mTOR → Cell division, cell proliferation, cell survival, angiogenesis, nutrient uptake, energy production
⑹ Type 5. GSK3
⑺ Type 6. CLK
3. G Protein-Coupled Receptors (GPCR)
⑴ Overall Structure
Figure 1. Structure of G Protein-Coupled Receptors
⑵ Component 1. Membrane Receptors (GPCR)
① Diversity of Cell Membrane Receptors
② Structure: Penetrates the cell membrane 7 times (7TM, 7 trans-membrane). In other words, there are 7 α-helices.
③ Attachment of G Proteins: G proteins are attached to the 5th and 6th transmembrane regions.
⑶ Composition 2. G Protein
① Location: Exposed to the cytoplasm, attached to the 5th and 6th transmembrane regions of GPCRs.
② Function: Converts GTP to GDP.
○ Activates enzymes that generate 2nd messengers after being activated by GPCRs, contributing to signal transduction.
○ Binds with GTP for activation, and with GDP for inactivation.
○ Activates 2nd messengers like PKA, PKC, PKG, opens or closes ion channels (olfaction).
○ There’s a connection between directly opening ion channels and sensitivity to olfaction.
③ Structure: Composed of three subunits: Gα, Gβ, Gγ.
○ Gβ and Gγ subunits are always together.
○ Upon GPCR activation, GDP bound to the αβγ complex is released, causing α and βγ subunits to dissociate, activating the G protein.
○ βγ subunit activates adenylate cyclase (AC) and phospholipase C (PLC).
④ Various types of α subunits exist.
⑤ Type 1. Gαs (stimulatory): Activates adenylate cyclase (AC).
○ 1st. G protein moves to GPCR and gets activated.
○ 2nd. αs subunit of G protein activates adenylate cyclase (AC).
○ 3rd. AC converts ATP to cAMP.
○ 4th. cAMP activates PKA, initiating phosphorylation cascade.
⑥ Type 2. Gαi (inhibitory): Inhibits adenylate cyclase (AC).
○ 1st. βγ complex dissociates from α subunit due to GPCR.
○ 2nd. αi subunit inhibits adenylate cyclase (AC).
○ 3rd. Down-signaling occurs.
○ Forms muscarinic receptors.
⑦ Type 3. Gq: Activates phospholipase C (PLC).
○ 1st. Signal molecule binding to G protein-coupled receptor activates phospholipase C (PLC).
○ 2nd. PLC breaks down PIP2 into DAG and IP3.
○ 3rd. Both DAG and IP3 act as secondary messengers, activating different pathways.
○ 4th. IP3 acts as ligand for IP3-gated channels on ER, releasing Ca2+ into the cytoplasm.
○ 5th. Released Ca2+ binds to calmodulin or acts as a secondary messenger to activate PKC and other proteins. DAG also influences protein phosphorylation.
○ 6th. G protein’s α subunit can hydrolyze GTP, stopping signal transmission.
⑧ Type 4. Gαt
⑨ Type 5. GαO: Inhibits adenylate cyclase (AC).
⑩ Type 6. Gαolf: Activates adenylate cyclase (AC).
⑪ Type 7. Gg
⑫ Type 8. G11: Activates phospholipase C (PLC).
⑬ Type 9. G12,13
⑷ Composition 3. Small GTPase
① Similar function as G proteins but smaller in size: About 1/10 the size of G proteins.
① Example 1. Rho: Attaches cell membrane receptors to the cytoskeleton, regulating cell shape and movement.
② Example 2. Ras
○ Activated by tyrosine kinases, involved in signal transduction pathways.
○ Important in activating MAPK.
○ Normal function: Cell proliferation, differentiation, survival.
○ Subtypes: H-Ras, K-Ras, N-Ras.
○ Ras genes are oncogenes.
③ Example 3. ARF1, ARF6: Involved in autophagosome formation.
⑸ Composition 4. Regulators
① PKA (Protein Kinase A)
○ Serine/threonine kinase activated by cAMP.
○ Increases fatty acid oxidation by acting on ligase.
② PKC (Protein Kinase C)
○ Kinase activated by DAG.
○ Phosphorylates glycogen synthase, among others.
③ PKG (Protein Kinase G)
○ Opens K+ channels and closes Ca2+ channels via PKG.
④ cAMP: A secondary messenger
○ There are also G proteins that regulate cAMP.
○ Serotonin can increase cAMP by more than 100 times.
○ Adenyl cyclase : Converts ATP to cAMP.
○ PDE (phosphodiesterase) : Breaks down cAMP.
⑤ Adenylyl Cyclase (AC)
○ AC converts ATP to cAMP.
○ cAMP directly activates PKA, a type of Ser/Thr kinase : Mainly in skeletal muscles.
○ When the signal from AC disappears, cAMP is converted to AMP by a phosphodiesterase.
○ Gαs : Activates adenyl cyclase.
○ Gαi : Inhibits adenyl cyclase.
⑥ Phospholipase C (PLC)
⑦ Calmodulin (CaM)
○ Extracellular Ca2+ / Intracellular Ca2+ = 10,000.
○ Found in the cytoplasm of all eukaryotic cells, from plants and fungi to protists.
○ Binding with Ca2+ changes its structure, enabling interaction with various intracellular proteins.
○ Particularly, Ca2+/calmodulin-dependent kinases (CaM-kinase) activated by calmodulin phosphorylate specific proteins, influencing various cellular responses.
○ Example: NO.
⑧ PIP2 : Phosphatidyl inositol 4,5-bisphosphate.
⑨ DAG : Diacylglycerol.
⑩ IP3 : Inositol triphosphate.
⑪ GAP (GTPase accelerating protein)
○ Assists Gα in GTPase function by Ras.
○ Inactivates G proteins.
⑫ GEF (Guanine-nucleotide exchange factor)
○ Catalyzes the binding of Ras and GTP.
○ Assists in the reactivation of G proteins.
○ GDP → GTP (i.e., brings in new GTP).
⑹ Example 1. Glycogen breakdown regulation : cAMP.
Figure 2. Schematic of the adrenaline signaling pathway [Footnote:2].
① 1st. Epinephrine (adrenaline) binds to a type of GPCR called epinephrine receptor.
② 2nd. G protein moves to the GPCR and gets activated.
③ 3rd. Gαs subunit of the G protein activates adenylyl cyclase (AC).
④ 4th. AC converts ATP to cAMP.
⑤ 5th. cAMP activates PKA, initiating a phosphorylation cascade.
⑥ 6th. Phosphorylation cascade eventually activates glycogen phosphorylase, leading to glycogen breakdown.
⑦ 7th. Glucose production.
⑺ Example 2. Metabotropic acetylcholine receptor (muscarinic receptor).
① Overview
○ Found at the terminal synapses of all parasympathetic postganglionic fibers.
○ Also found in the brain, heart, and smooth muscles.
○ Distributes throughout the autonomic ganglia except in cardiac muscle fibers.
○ Responds to muscarine.
○ Type 1: M1, M2, M5 : Excitatory receptors.
○ Type 2: M3, M4 : Inhibitory receptors.
② Mechanism
○ 1st. Gαi is activated.
○ 2nd. Acetylcholine (Ach) binding to the muscarinic receptor causes separation of the βγ subunits from the α subunit.
○ 3rd. αi subunit inactivates adenylyl cyclase : Interaction with Gαs protein.
○ 4th. β-γ complex of the G protein binds to K+ ion channels, leading to K+ efflux : Slows heart rate.
③ Examples
○ Example 1: Acetylcholine receptors found in the parasympathetic nervous system.
○ Example 2: Found in cardiac cells and postganglionic parasympathetic neurons.
○ Example 3: Nitric oxide (NO) and vascular relaxation.
④ Inhibitors
○ Atropine : Muscarinic antagonist, sympathetic nerve stimulation.
○ Sarin, DIFP, Tabun : Covalent inhibitors of acetylcholine esterase.
⑻ Example 3. Adrenergic receptor (adrenoceptor).
① Binds catecholamine hormones such as norepinephrine, epinephrine, beta-blockers, beta-agonists, alpha-agonists.
② Adrenergic receptors mainly located in arterioles, with different functions and types based on location.
○ Liver cells : Epinephrine beta receptors → Increase blood glucose.
○ Skeletal muscle blood vessels : Epinephrine beta receptors → Vasodilation.
○ Intestinal blood vessels : Epinephrine alpha receptors → Vasoconstriction.
○ Cardiac muscles and other smooth muscle arterioles : Epinephrine beta receptors → Arteriolar dilation → Increased blood flow → Contraction of cardiac muscles and smooth muscles.
○ Visceral organ arterioles : Epinephrine alpha receptors → Arteriolar constriction → Decreased blood flow to visceral organs → Visceral relaxation.
③ Total of 9 subtypes : α1A, α1B, α1D, α2A, α2B, α2C, β1, β2, β3.
○ α1 couples with Gαq protein. Found in arterioles supplying visceral organs.
○ α2 couples with Gαi protein.
○ All β receptors couple with Gαs protein.
○ β1 : Found only in the heart. Located in sinoatrial node and ventricles.
○ β2 : Supplies skeletal muscles and located in blood vessels.
○ Both β2 and β3 also couple with Gαi protein.
⑼ Example 4. Inhibition of G protein function.
① Cholera toxin : AB toxin
○ 1st. B subunit of AB toxin reacts with GPCR, A enters the cell.
○ 2nd. GPCR activates Gαs.
○ 3rd. Gαs reacts with ADP-ribose, reducing GTPase activity.
○ 4th. Reduced GTPase activity increases adenylyl cyclase activity.
○ 5th. Adenylyl cyclase generates cAMP from ATP.
○ 6th. Increased cAMP activates PKA.
○ 7th. ATP binds to the R domain of CFTR channel via PKA, opening the channel.
○ 8th. Increased Cl- secretion and water efflux cause diarrhea and dehydration.
② Pertussis toxin
○ 1st. ADP-ribose reacts with Gi, decreasing Gi activity.
○ 2nd. Adenylyl cyclase activity increases.
○ 3rd. Increased cAMP decreases secretion of chemical messengers in infected cells.
○ 4th. Diminished immune cell recruitment increases infection and triggers respiratory issues.
⑽ Example 5. Other examples of GPCRs.
④ Somatostatin receptor : SSTR1 ~ SSTR5
⑤ [FSH Receptor](https://jb243.github.io/pages/553#:~:text=%E2%91%B6%20%EC%97%AC%ED%8F%AC%EC%9E%90%EA%B7%B9%ED%98%B8%EB%A5%B4%EB%AA%AC(-,FSH,-%2C%20follicle%20stimulating)
⑥ Mechanisms Preventing Multiple Crystallization During Sea Urchin Development
4. Tyrosine Kinase Receptors (receptor tyrosine kinase, RTK)
⑴ Component 1. RTK
① TKD : tyrosine kinase domain
⑵ Component 2. Regulators
① rho : Attaches cell membrane receptors to the cytoskeleton to regulate cell shape and movement
② Ras ( rat sarcoma )
○ Activated by tyrosine kinase to participate in signal transduction pathways
○ Plays an important role in activating MAPK
○ Normal functions : Cell proliferation, cell differentiation, cell survival
○ Ras is divided into H-Ras, K-Ras, N-Ras, etc.
○ One of the oncogenes
③ PI3K(PI3-kinase) : Converts PI(4,5)-P2 to PI(3, 4, 5)P3, allowing PDK1 and Akt to bind
④ JAK-STAT : Involves STAT1,2, SH2
⑤ MAPK
⑥ Src family
⑦ FAK
⑧ myc
⑶ Mechanism
① 1st. Ligand binding : Growth factors bind to receptors
② 2nd. Autophosphorylation : Each receptor can phosphorylate itself while transferring phosphate to the opposite tyrosine
○ Has an ATP binding site, so phosphorylation uses ATP
③ 3rd. Proteins like GRB2 bind and locate Sos factor
○ Sos factor : Acts as a GEF, separating GDP from Ras and binding GTP to activate it
○ GEF (guanine-nucleotide exchange factor) : Aids in G-protein reactivation. GDP → GTP (i.e., brings in new GTP)
④ 4th. Sos factor activates Ras, and activated Ras activates Raf
○ Nearly all receptor tyrosine kinases that bind growth factors activate Ras protein
⑤ 5th. Raf catalyzes MEK phosphorylation
○ Raf is a serine/threonine kinase
⑥ 6th. MAPK is activated during MEK phosphorylation and then moves into the nucleus
○ MAPK : Also known as ERK, responds sequentially
○ ERK1/2 : Inhibits feedback from GRB2 / SOS
⑦ 7th. Inactive transcription factor myc becomes activated, and cyclin D is generated
⑧ 8th. Such signaling is halted by removing phosphate from phosphorylated sites through tyrosine dephosphorylase
⑶ Tyrosine Kinase Inhibitors
① imatinib (Glivec)
② dasatinib (Sprycel)
③ sunitinib (Sutent)
④ nilotinib (Tasigna)
⑤ sorafenib (Nexavar)
⑥ temsirolimus (Torisel)
⑦ nintedanib : Treatment for idiopathic pulmonary fibrosis
⑧ pirfenidone : Treatment for idiopathic pulmonary fibrosis
⑷ Example 1. EGFR (epidermal growth factor receptor)
① Component 1. EGFR
○ Also known as ErbB1 or HER-1
○ Structure : 170 kDa glycoprotein
○ This protein is composed of 1186 amino acids, forming 1 polypeptide chain
○ Initial precursor consists of 1210 amino acids, forming 1 polypeptide chain
○ 60-80% of colorectal cancers overexpress EGFR
② Component 2. EGF
○ Structure : 6 kDa. Human EGF consists of 53 amino acids
③ EGFR Signaling Pathway
○ 1st. When EGF and EGFR bind, it causes a change in structure, activating TKD.
○ 2nd. Various types of signaling proteins bind to phosphorylated EGFR
○ Type 1: SH2 (src homology-2) : The N-terminus of SH2 recognizes the sequence of tyrosine.
○ Type 2: Shc’s PTB (phosphotyrosine binding) domain : The C-terminus of the PTB domain binds.
○ 3rd. Major downstream signaling
○ Ras → Raf → ERK
○ PI3K → Akt → mTOR
Figure 3. EGFR signaling pathway
④ Positive feedback regulators
○ ERBB ligands : TGFα, HB-EGF, etc., increase expression after the signaling pathway
⑤ Negative feedback regulators
○ DEP (density-enhanced phosphatase-1)
○ SOCS5 (cytokine signaling-5)
⑥ Inhibitors
○ Gefitinib (Iressa) : An anticancer drug that inhibits EGFR-TKI (EGFR-tyrosine kinase inhibitor). FDA-approved
○ Erlotinib (Tarceva)
○ Cetuximab (Erbitux) : FDA-approved
○ IgG1 isotype
○ Binding site : Q384, Q408, H409, K443, K465, I467, S468, F352, D355, P387
○ Has immunogenic activity
○ Panitumumab (Vectibix) : FDA-approved
○ IgG2 isotype
○ Binding site : P349, P362, D355, F412, I438
○ No immunogenic activity
○ Lapatinib (Tyverb) : Directly inhibits downstream signaling by inhibiting TKD. FDA-approved
○ Afatinib : Directly inhibits downstream signaling by inhibiting the tyrosine-kinase domain. FDA-approved
○ Sapitinib
⑸ Example 2. HER2 (erbB-2) : Also known as CD340, Neu, Erbb2 (rodent), ERBB2 (human)
① Structure : (Extracellular) I - II - III - IV - Transmembrane domain - TKD (Intracellular)
○ II : Dimerization domain
② Function
○ Overexpression of HER2 leads to excessive cell proliferation through autophosphorylation : Associated with poor prognosis, tumor formation, etc.
○ Overexpressed in 15-40% of ovarian cancer cases
③ Mechanism : Utilizes PI3-kinase signaling
④ Positive feedback regulators
○ ERBB2 : Once activated, subsequent activation is facilitated
○ Heterodimer containing ERBB2
○ ERBB ligands : TGFα, HB-EGF, etc., increase expression after the signaling pathway
⑤ Inhibitors
○ Pertuzumab : Inhibits II, inhibiting receptor dimerization. FDA-approved
○ Trastuzumab, margetuximab : Inhibits IV. Associated with ADCC. FDA-approved
○ Trastuzumab emtansine (T-DM1) : Conjugates anticancer drug with trastuzumab. FDA-approved
○ Trastuzumab deruxtecan : Conjugates anticancer drug with trastuzumab. FDA-approved
○ Lapatinib : Directly inhibits downstream signaling by inhibiting TKD. FDA-approved
○ Afatinib : Directly inhibits downstream signaling by inhibiting TKD. FDA-approved
○ Neratinib : Directly inhibits downstream signaling by inhibiting TKD. FDA-approved
○ Sapitinib
○ CI-1033
⑹ Example 3. HER3 (erbB-3)
① Inhibitors : Sapitinib
⑺ Example 4. IGF-1R (insulin-like growth factor receptor)
① Structure
○ Extracellular ligand-binding domain : Contains two α subunits
○ Transmembrane domain
○ Cytoplasmic domain : Contains two β subunits
○ Total of 3 disulfide bonds : α-α, α-β, α-β
○ β subunits function as tyrosine kinases
② IGF-1R can bind to ligands IGF-1 and IGF-2
③ When IGF-1R is activated, the following three signaling pathways are activated
○ STAT3
○ PI3K → AKT (inhibited by PTE) → mTOR → S6K
○ GRB2 → Ras / Raf → MEK → MAPK
④ IGF-1R promotes malignant tumors
⑤ Inhibitors : AXL1717, linsitinib (currently in phase 3 trials)
⑻ Example 5. IR (insulin receptor)
① Structure
○ Extracellular ligand-binding domain : Contains two α subunits
○ Transmembrane domain
○ Cytoplasmic domain : Contains two β subunits
○ Total of 3 disulfide bonds : α-α, α-β, α-β
○ β subunits function as tyrosine kinases
② Experiment : In cancer cells like HepG2, both IGF-1R and IR are overexpressed, forming IGF-1R/IR heterodimers
○ IGF-1R homodimer : Can bind to ligands IGF-1 and IGF-2
○ IR homodimer : Can bind to ligands IGF-2 and insulin
○ IGF-1R/IR heterodimer : Can bind to ligands IGF-1, IGF-2, and insulin
○ IGF-1R/IR heterodimer has a broad ligand-binding site, making it sensitive to anticancer agents
○ Anti-IGF1R antibody can inhibit the proliferation of cancer cells dependent on IGF-1R/IR heterodimers
⑼ Example 6. Bruton’s tyrosine kinase : The drug ibrutinib targets this.
5. Serine/Threonine Kinase Receptors
⑴ Type 1. TGF-β Receptors
① 1st. Formation of TGF-βRⅠ by binding TGF-β1 ligand and TGF-βRⅡ receptor
② 2nd. Activation of Smad2, Smad3 by TGF-βRⅠ : Inhibited by Smad7
③ 3rd. Activated Smad2, Smad3 act as transcription factors by binding Smad4
④ Function : Involved in wound healing, angiogenesis, immune regulation, cancer development
6. Intracellular Receptors
⑴ Overview
① Binding : Lipophilic ligands (e.g., steroid hormones)
② Location : Inside the cytoplasm
③ Mechanism : Direct entry into the nucleus → Transcription factors
⑵ Example 1. PPAR (Peroxisome Proliferator-Activated Receptor)
① Structure : A/B domain (N-terminus) + C domain (conserved DNA-binding domain) + E domain (ligand-binding C-terminus)
② Type 1. PPARα : Abundant in liver, skeletal muscle, kidney, heart, and blood vessels; low in fat and cartilage
③ Type 2. PPARβ/δ : Expressed throughout the body, relatively high expression in brain, liver, and intestines
④ Type 3. PPARγ : Expressed in mammalian adipose tissue, vascular smooth muscle, heart muscle; important transcription factor regulating cell division
⑶ Example 2. [Prostaglandin Receptor (PtgR)](https://jb243.github.io/pages/86#:~:text=%E2%97%8B%204th.-,%ED%94%84%EB%A1%9C%EC%8A%A4%ED%83%80%EA%B8%80%EB%9E%80%EB%94%98,-%3A%20%EC%97%BC%EC%A6%9D%EB%B0%98%EC%9D%91(%EC%97%B4%20%EB%B0%9C%EC%83%9D)
① Prostaglandin : Causes inflammation (fever), mucous secretion, headaches, blood clotting, smooth muscle contraction (uterine contraction in females)
② Prostaglandin is produced in almost all cells and acts as a local regulator due to its unstable molecular structure
③ Immune cells like mast cells transport prostaglandin to neighboring cells’ cytoplasm to trigger inflammation
⑷ Example 3. Estrogen Receptor(ER, estrogen receptor)
○ Pathway : Binds to plasma transport proteins, moves to tissues → Intracellular receptor → Gene expression
○ Synthesized and secreted as needed
○ Steroid hormones, thyroid hormone, nitric oxide (NO), adrenal cortex hormones
② Genetic Pathway : Estrogen binds to ERα or ERβ, acts on target DNA’s ERE or AP-1 for transcriptional activity
③ Non-genetic Pathway : Estrogen + ERα/ERβ or Estrogen + GPR30 activate signaling pathways involving MAPK, cAMP
⑸ Example 4. Granzyme
① A type of proteolytic enzyme, enters infected cells through endocytosis
② Induces apoptosis in target cells, cleaving nuclei and cytoplasm
⑹ Example 5. cGAS-STING pathway
① 1st. Binding of dsDNA (double-strand DNA) and cGAS (cyclic GMP-AMP synthase) enzyme
② 2nd. dsDNA-cGAS complex binds to cGMP
○ Inhibited by ENPP1 binding
③ 3rd. dsDNA-cGAS-cGMP complex activates STING (stimulator of interferon gene)
○ STING : Also known as TMEM173, MPYS/MITA/ERIS. Encoded by the STING1 gene
④ 4th. Activated STING moves to the Golgi apparatus
⑤ 5th. TBK1/IRF3, IKK-IκB signaling pathways activate
⑥ 6th. Ultimately releases IFN-β and IL-6 cytokines
⑦ Function
○ Innate immune response : Generates type I interferon when cells are infected by pathogens through this pathway
○ Prevents spread of infection from infected cells to neighboring cells
7. Ion Channels
⑴ Ligand-Gated Ion Channels
① Nicotinic Acetylcholine Receptor (nAhR) : Also known as ionotropic acetylcholine receptor
○ Overview
○ Found in autonomic ganglia, neuromuscular junctions, central nervous system, etc.
○ Not present in sinoatrial node, cardiac muscle fibers
○ Enables rapid neural transmission as an excitatory receptor
○ Upon acetylcholine binding, both Na+ and K+ can pass through, with Na+ permeability being greater, causing depolarization
○ Named “nicotinic” due to its response to nicotine
○ Structure : Pentamer
○ Muscle-type : (α1)2β1δε or (α1)2β1δγ
○ Ganglion-type : (α3)2(β4)3
○ Heteromeric CNS-type : (α4)2(β2)3
○ Further CNS-type : (α3)2(β4)3
○ Homomeric CNS-type : (α7)5
○ Types
○ N1 Receptor : Located in neuromuscular junctions
○ N2 Receptor : Found in brain, dendrites, sympathetic nerves
○ Examples
○ Sodium channels involved in generating action potentials
○ Acetylcholine receptors in skeletal muscles
○ Inhibitors
○ Sarin, DIFP, tubocurarine : Irreversible inhibitors of acetylcholinesterase
○ Curare : Closes nicotinic receptors, muscle relaxant
② Na+ Channel
○ Plant tube-closing response to Cr-La : Inhibitor of sodium channels, acts as a substrate-dependent sodium channel blocker
⑵ Voltage-Gated Ion Channels (e.g., Axons)
① Tetrodotoxin : Irreversible inhibitor of voltage-gated Na+ channels
② Tetraethylammonium : Blocks voltage-gated K+ channels
③ Botulinum toxin : Blocks voltage-gated Ca2+ channels at neuromuscular junctions → Inhibits acetylcholine release → Causes muscle paralysis
⑶ Mechanosensitive Ion Channels
8. Adhesion Receptors
⑴ Type 1. Integrin(integrin)
① 1st. Src, PYK2, FAK, SOS, GRB2, RACK1
② 2nd. Rac + GTP
③ 3rd. PAK
④ 4th. Raf1, MEK1
⑤ 5th. Erk1/2, MSK1/2
⑥ 6th. Fos, Ets, Elk, HIF1, STAT3, CREB, c-Jun
9. Other Receptors
⑴ TNF Receptors
① TNFR
○ TNFR1 : Associated with inflammation, apoptosis, 55 kDa
○ TNFR2 : Associated with anti-inflammatory response, 75 kDa
○ Additionally, receptors with similar structures that perform inflammatory responses constitute the TNFR superfamily (e.g. Fas receptor)
② TNF (tumor necrosis factor)
○ TNF-α : Exists in membrane-bound form (mTNF-α) and soluble form (sTNF-α) that dissolves in water
○ TNF-β
③ Cell death signaling pathway
○ TNFR → TRADD → FADD → Caspase 8 → Caspase 3 → apoptosis
○ TNFR → TRADD → TRAF2 → clAPS → apoptosis
○ TNFR → TRADD → TRAF2 → MEKK1/4 → MEKK4/7 → JNK → apoptosis
○ 1st. Fas or TNF binds to receptors
○ 2nd. CASP8 (caspase 8) binds with an adaptor to form DISC
○ 3rd. DISC activates caspase 3
○ 4th. CASP3 (caspase 3) initiates cell death
④ Cell survival and inflammatory response signaling pathway
○ TNFR → TRAF2 → MEKK1/4 → MEKK4/7 → JNK → AP-1 → inflammation & survival
○ TNFR → TRAF2 → ASK1 → MEKK4/7 → JNK → AP-1 → inflammation & survival
○ TNFR → TRAF2 → RIP → MEKK3/6 → MAPK → inflammation & survival
○ TNFR → TRAF2 → NIK → IKK → NF-κB → inflammation & survival
○ TNFR → TRAF2 → RIP → IKK → NF-κB → inflammation & survival
⑵ Toll-like Receptor(TLR)
① Types of TLRs
○ TLR-1 : multiple triacyl lipopeptide
○ TLR-2 : lipoteichoic acid. Activates innate immunity
○ TLR-3 : Recognizes dsRNA present in viruses
○ TLR-4 : Recognizes LPS (lipopolysaccharide) from gram-negative bacteria
○ TLR-5 : Recognizes flagellin, a component of bacterial flagella
○ TLR-6 : multiple diacyl lipopeptide
○ TLR-7 : Recognizes single-stranded RNA
○ TLR-8 : Recognizes small synthetic compounds and single-stranded RNA
○ TLR-9 : Recognizes unmethylated CpG DNA sequences and oligodeoxynucleotide DNA
② Pathway 1. MyD88-dependent pathway
○ Overview: Mechanism pathway via signal transduction. Activates NF-κB. Increases TNF-α and IL-1β
○ TLR → MyD88 → TRAF6 → NF-κB → NF-κB translocates to the nucleus
○ TLR → MyD88 → TRAF6 → MAPK → AP-1
③ Pathway 2. TRIF-dependent pathway
○ Overview: Mechanism pathway via endosome
○ TLR → TAM, TRIF → IRF3 → IRF3 translocates to the nucleus → type I IFN
○ TLR → TAM, TRIF → TRAF6 → NF-κB → NF-κB translocates to the nucleus
○ TLR → TAM, TRIF → TRAF6 → MAPK → AP-1
⑶ Notch signaling
① Function: Determines cell fate, cell division, cell differentiation, cell death, etc.
② Mammals have four types of Notch receptors: NOTCH1, NOTCH2, NOTCH3, NOTCH4
⑷ Wnt signaling: Associated with Frizzled receptor
⑸ Hedgehog signaling
⑹ Enzyme-coupled receptor
① Case 1: Receptor itself has catalytic domain
② Case 2: Enzyme assists
③ Both cases lead to ECR dimerization for signal transduction
⑺ AGE-RAGE
⑻ Rap1
⑼ NOD-like receptor
⑽ YAP/TAZ signaling
⑾ Hippo signaling
⑿ FGFR pathway
⒀ E-cadherin-integrin pathway
10. Signal Transduction Enhancers
⑴ AMPK: A769662
11. Signal Transduction Inhibitors
⑴ mTORC1 inhibitor: rapamycin (sirolimus)
⑵ MEK1/2 inhibitor: trametinib (Mekinist), cobimetinib, refametinib
⑶ ERK1/2 inhibitor: MK-8353, SCH772984
⑷ AKT1/2 inhibitor: MK-2206
⑸ MAPK9 inhibitor: AS602801
⑹ PI3K inhibitor: LY294002, taselisib, alpelisib, MK-2206, idelalisib (CAL-101), dactolisib (BEZ-235), everolimus, pictilisib (GDC-0941), apitolisib (GDC-0980)
⑺ IκB inhibitor: Bortezomib
⑻ sPLA2-IIa inhibitor: cFLSYR, c(2NapA)LS(2NapA)R
⑼ AMPK inhibitor: dorsomorphin
⑽ Phosphorylation signal inhibitors: lapatinib
⑾ PARP1/2 inhibitor: olaparib
⑿ PLK4 inhibitor: CFI400945
⒀ p38 inhibitor: VX-745
⒁ CHEK1/2 inhibitor: AZD-7762
① CHEK1-selective inhibitor: SAR-020106, rabusertib
② CHEK2-selective inhibitor: CCT-241533
⒂ BRAF inhibitor: dabrafenib, vemurafenib (Zelboraf), PLX4720
⒃ JNK inhibitor: JNK-IN-8
⒄ WEE1, PLK1 inhibitor: MK-1775
⒅ BCL2, BCL-XL, BCL-W inhibitor: navitoclax
⒆ TGF-βR inhibitor: RepSox
⒇ Tyrosine phosphorylase inhibitors: imatinib (Glivec), dasatinib (Sprycel), sunitinib (Sutent), nilotinib (Tasigna), sorafenib (Nexavr), temsirolimus (Torisel)
Input : 2021.01.24 23:48
Modified : 2022.06.13 14:05