○ When triggered by GPCR, the GDP bound to the αβγ complex is released, leading to the separation of the α subunit and the βγ complex, thereby activating the G-protein.

○ The βγ complex activates adenylyl cyclase (AC) and phospholipase C (PLC).

④ Various types of α subunits exist as follows.

⑤ Type 1. Gα_s (stimulatory)

○ Activation of adenylyl cyclase (AC): The second messenger is cAMP.

○ 1^st. G protein moves to GPCR and gets activated.

○ 2^nd. α_s subunit of G protein activates adenylyl cyclase (AC).

○ 3^rd. AC converts ATP to cAMP.

○ 4^th. cAMP activates PKA, initiating phosphorylation cascade.

○ Examples: β-adrenergic (epinephrine) receptor, glucagon receptor, serotonin receptor, vasopressin receptor

⑥ Type 2. Gα_i (inhibitory)

○ Inhibition of adenylyl cyclase (AC): The second messenger is cAMP.

K⁺ Channel: Activated by G_βγ. The second messenger is the change in membrane potential.

○ 1^st. The βγ complex is separated from the α subunit by GPCR.

○ 2^nd. α_i subunit inhibits adenylyl cyclase (AC).

○ 3^rd. Down-signaling occurs.

○ Examples: α₂-adrenergic receptor, muscarinic acetylcholine receptor

⑦ Type 3. Gα_q

○ Activation of PLC (phospholipase C): The second messengers are IP₃ and DAG.

○ 1^st. When a signaling molecule binds to a G-protein-coupled receptor, it activates phospholipase C (PLC).

○ 2^nd. The inositol phospholipid PIP₂ is hydrolyzed by PLC into DAG (diacylglycerol) and inositol IP₃.

○ 3^rd. Both DAG and IP₃ act as secondary messengers, activating different pathways.

○ 4^th. IP₃ rapidly diffuses into the cytoplasm and acts as a ligand for the IP₃-gated channels on the smooth endoplasmic reticulum membrane, facilitating the release of Ca²⁺ from the smooth endoplasmic reticulum into the cytoplasm.

○ 5^th. The released calcium binds to calmodulin or acts as a second messenger to activate PKC (phosphokinase C) and other proteins. DAG also participates in activating protein kinases.

○ 6^th. The α subunit of the G-protein possesses GTPase activity, hydrolyzing GTP to GDP and P_i, which allows it to terminate signal transduction spontaneously.

○ Example: α₁-adrenergic receptor

⑧ Type 4. Gα_t

○ Activation of cGMP phosphodiesterase: The second messenger is cGMP.

○ Example: Rhodopsin in rod cells.

⑨ Type 5. Gα_O

○ Inhibition of adenylyl cyclase (AC): The second messengers are IP₃ and DAG.

○ Example: Acetylcholine receptor in endothelial cells.

⑩ Type 6. Gα_olf

○ Activation of adenylyl cyclase (AC): The second messenger is cAMP.

○ Example: Olfactory receptor.

⑪ Type 7. G_g

⑫ Type 8. G₁₁

○ Activation of phospholipase C (PLC).

⑬ Type 9. G_12,13

⑷ Component 3. Small GTPase

① Similar function as G proteins but smaller in size: About 1/10 the size of G proteins.

② Example 1. Rho: Attaches cell membrane receptors to the cytoskeleton, regulating cell shape and movement.

③ Example 2. Ras (rat sarooma)

○ A GPCR activated by tyrosine kinase, involved in the signal transduction pathway.

○ Plays an important role in activating MAPK.

○ Normal functions: Cell proliferation, cell differentiation, cell survival.

○ Ras is furtherdivided into H-Ras, K-Ras, N-Ras, etc.

○ Ras genes are one of oncogenes.

④ Example 3. ARF1, ARF6: Involved in the early formation of the autophagosome.

⑸ Component 4. Related regulators

① PKA (Phosphokinase A)

○ Serine/threonine kinase activated by cAMP.

○ PKA acts on ligase to oxidize fatty acids.

② PKC (Phosphokinase C)

○ Kinase activated by DAG.

○ Phosphorylates glycogen synthase, etc.

③ PKG (Phosphokinase G)

○ PKG opens K⁺ channels and closes Ca²⁺ channels.

④ cAMP: A secondary messenger

○ There are also G proteins that regulate cAMP.

○ Serotonin can increase cAMP by more than 100 times.

○ Adenylyl 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.

○ Gα_s: Activates adenyl cyclase.

○ Gα_i: Inhibits adenyl cyclase.

⑥ Phospholipase C (PLC)

⑦ Calmodulin (CaM): Ca²⁺-binding protein

○ Extracellular Ca²⁺ / Intracellular Ca²⁺ = 10,000.

○ Found in the cytoplasm of all eukaryotic cells, including plants, fungi, and protists.

○ Binding with Ca²⁺ changes its structure, enabling its binding with various intracellular proteins.

○ Particularly, Ca²⁺/calmodulin-dependent kinases (CaM-kinase) activated by calmodulin phosphorylate specific proteins, influencing various cellular responses.

○ Example: NO (Nitric oxide).

⑧ PIP₂: Phosphatidyl inositol 4,5-bisphosphate.

⑨ DAG: Diacylglycerol.

⑩ IP₃: Inositol triphosphate.

⑪ GAP (GTPase accelerating protein)

○ Assists Gα in GTPase function via 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

① 1^st. Epinephrine (adrenaline) binds to the epinephrine receptor, a type of GPCR.

② 2^nd. G protein moves to the GPCR and gets activated.

③ 3^rd. α_s subunit of the G protein activates adenylyl cyclase (AC).

④ 4^th. AC converts ATP to cAMP.

⑤ 5^th. cAMP activates PKA, initiating a phosphorylation cascade.

⑥ 6^th. Phosphorylation cascade eventually activates glycogen phosphorylase, leading to glycogen breakdown.

⑦ 7^th. Glucose production.

⑺ Example 2. Metabotropic acetylcholine receptor (muscarinic receptor)

① Overview

○ Found at the terminal synapses of all postsynaptic nerve fibers in the parasympathetic nervous system.

○ Also found in the brain, heart, and smooth muscles.

○ Present in GPCR and the sinoatrial node but not in cardiac muscle fibers.

○ Responds to muscarine.

○ Type 1. M1, M2, M5: Excitatory receptors

○ Type 2. M3, M4: Inhibitory receptors

② Mechanism

○ 1^st. Gα_i is activated.

○ 2^nd. When acetylcholine (Ach) binds to muscarinic receptors, the βγ subunit separates from the α subunit.

○ 3^rd. The α_i subunit inactivates adenylyl cyclase, acting antagonistically to the Gα_s protein.

○ 4^th. The β-γ complex of the G-protein binds to K⁺ ion channels, causing K⁺ to diffuse out of the cell, leading to a decrease in heart rate.

③ Examples

○ Example 1. Acetylcholine receptors found in the parasympathetic nervous system.

○ Example 2. Primarily found at the junctions between cardiac cells and parasympathetic nerves.

○ Example 3. Nitric oxide (NO) and vascular relaxation model.

④ Inhibitors

○ Atropine: Antidote for muscarinic toxins. Stimulates sympathetic nerve activity.

○ Sarin, DIFP, Tabun: Covalent inhibitors of acetylcholinesterase.

⑻ Example 3. Adrenergic receptor (adrenoceptor)

① Binds to catecholamine hormones, norepinephrine, epinephrine, beta-blockers, β₂ agonists, and α₂ 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 other smooth muscles.

○ Visceral organ arterioles: Epinephrine alpha receptors → Arteriolar constriction → Decreased blood flow to visceral organs → Visceral muscle relaxation.

③ Total of 9 subtypes: α_1A, α_1B, α_1D, α_2A, α_2B, α_2C, β₁, β₂, β₃.

○ α₁ couples with Gα_q protein. Found in arterioles supplying blood to visceral organs.

○ α₂ couples with Gα_i protein.

○ All β receptors couple with Gα_s protein.

○ β₁: Found exclusively in the heart, distributed in the sinoatrial node and ventricular muscle.

○ β₂: Supplies blood to the musculoskeletal system and is distributed in arterioles.

○ Both β₂ and β₃ also couple with Gα_i protein.

⑼ Example 4. Inhibition of G protein function

① Cholera toxin: AB toxin

○ 1^st. B subunit of AB toxin reacts with GPCR, and A enters the cell.

○ 2^nd. GPCR activates Gα_s.

○ 3^rd. Gα_s reacts with ADP-ribose, reducing GTPase activity.

○ 4^th. Reduced GTPase activity increases adenylyl cyclase activity.

○ 5^th. Adenylyl cyclase generates cAMP from ATP.

○ 6^th. Increased cAMP activates PKA.

○ 7^th. ATP binds to the R domain of CFTR channel via PKA, opening the channel.

○ 8^th. Increased Cl^- secretion leads to water release through osmosis, causing diarrhea and dehydration.

② Pertussis toxin

○ 1^st. ADP-ribose reacts with G_i/o, decreasing G_i/o activity.

○ 2^nd. Adenylyl cyclase activity increases.

○ 3^rd. Increased cAMP reduces the secretion of chemotactic substances in infected cells.

○ 4^th. Diminished immune cell recruitment increases infection and triggers respiratory diseases.

⑽ Example 5. Other examples of GPCRs.

① Norepinephrine receptor in brown adipose tissue

② Transduction in rod cells

③ Olfactory nerve cells

④ Somatostatin receptors: SSTR1 ~ SSTR5

⑤ FSH receptor

⑥ Slow block mechanisms for polyspermy during sea urchin development

4. Tyrosine Kinase Receptors (receptor tyrosine kinase, RTK)

⑴ Component 1. RTK

① TKD: Tyrosine kinase domain

⑵ Component 2. Related regulators

① rho: Attaches cell membrane receptors to the cytoskeleton to regulate cell shape and movement.

② Ras (rat sarcoma)

○ A GPCR activated by tyrosine kinase, involved in the signal transduction pathway.

○ Plays an important role in activating MAPK.

○ Normal functions: Cell proliferation, cell differentiation, cell survival.

○ Ras is furtherdivided into H-Ras, K-Ras, N-Ras, etc.

○ Ras genes are one of 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: STAT1,2, SH2 are involved.

⑤ MAPK

⑥ Src family

⑦ FAK

⑧ Myc

⑶ Mechanism

① 1^st. Ligand binding: Growth factors bind to receptors.

② 2^nd. Autophosphorylation: Each receptor can phosphorylate itself while transferring phosphate to the opposite tyrosine.

○ Has an ATP binding site, so phosphorylation uses ATP.

③ 3^rd. Mediating proteins like GRB2 bind, facilitating the recruitment of the 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 4^th. Sos factor activates Ras, and activated Ras activates Raf.

○ Nearly all receptor tyrosine kinases that bind growth factors activate Ras protein.

⑤ 5^th. Raf catalyzes MEK phosphorylation.

○ Raf is a serine/threonine kinase.

⑥ 6^th. MAPK is activated during MEK phosphorylation and then moves into the nucleus.

○ MAPK: Reacts sequentially and is also known as ERK.

○ ERK1/2: Feedback inhibition of GRB2 / SOS.

⑦ 7^th. The previously inactive transcription factor Myc is now activated, leading to the production of Cyclin D.

⑧ 8^th. The above 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 medication for pulmonary fibrosis.

⑧ Pirfenidone: Treatment medication for 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

○ Protein composition: Consists of a single polypeptide made up of 1,186 amino acids.

○ Initial precursor: Consists of a single polypeptide made up of 1,210 amino acids.

○ 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

○ 1^st. When EGF and EGFR bind, it causes a change in structure, activating TKD.

○ 2^nd. The following 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. PTB (phosphotyrosine binding) domain of Shc: The C-terminus of the PTB domain binds.

○ 3^rd. Major downstream signaling

○ Ras → Raf → ERK

○ PI3K → Akt → mTOR

Figure 3. EGFR signaling pathway

④ Positive feedback regulators

○ ERBB ligands, such as TGFα and HB-EGF, show increased expression following the above signaling pathways.

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, such as TGFα and HB-EGF, show increased expression following the above signaling pathways.

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 1^st. The TGF-β1 ligand binds to the TGF-βRⅡ receptor, forming the TGF-βRⅠ complex.

② 2^nd. The TGF-βRⅠ complex activates Smad2 and Smad3: This process is Inhibited by Smad7.

③ 3^rd. Activated Smad2 and 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 (an evolutionarily conserved DNA-binding domain) + E domain (hormone-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, stomach, and colon.

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)

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 such as macrophages facilitate the transfer of prostaglandins into the cytoplasm of neighboring cells to induce an inflammatory response.

⑷ Example 3. Estrogen Receptor(ER, estrogen receptor)

① Lipophilic hormone

○ Pathway: Binds to plasma transport proteins and moves to tissues → Intracellular receptor → Gene expression

○ Synthesized and secreted as needed.

○ Steroid hormones, thyroxine, nitric oxide (NO), adrenal cortex hormones

② Genetic Pathway: Estrogen binds to ERα or ERβ and acts on ERE or AP-1 within target DNA to activate transcription.

③ Non-genetic Pathway: Estrogen + ERα/ERβ or Estrogen + GPR30 activates signaling pathways involving MAPK and cAMP.

⑸ Example 4. Granzyme

① A type of protease that enters infected cells through intracellular uptake.

② Induces apoptosis in target cells, cleaving nuclei and cytoplasm.

⑹ Example 5. cGAS-STING pathway

① 1^st. dsDNA (double-stranded DNA) binds with the cGAS (cyclic GMP-AMP synthase) enzyme.

② 2^nd. dsDNA-cGAS complex binds to cGMP.

○ Binding is inhibited by ENPP1.

③ 3^rd. dsDNA-cGAS-cGMP complex activates STING (stimulator of interferon gene).

○ STING: Also known as TMEM173, MPYS/MITA/ERIS. Encoded by the STING1 gene.

④ 4^th. Activated STING moves to the Golgi apparatus.

⑤ 5^th. TBK1/IRF3, IKK-IκB signaling pathways are activated.

⑥ 6^th. Ultimately IFN-β and IL-6 cytokines are released.

⑦ Function

○ Innate immune response: Through this pathway, type I interferon is produced when a cell is infected by an intracellular pathogen.

○ Prevents the spread of the infection source from the infected cell 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, and Tabun: Covalent inhibitors of acetylcholinesterase.

○ Curare: Blocks nicotinic receptors, acting as a skeletal muscle relaxant.

② Na⁺ Channel

○ Plant-derived tubocurarine: Acts as a substrate-dependent sodium channel inhibitor.

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

① Auditory receptor

② Equilibrium (vestibular) receptor

③ Cutaneous sensory receptor

8. Adhesion Receptors

⑴ Type 1. Integrin

① 1^st. Src, PYK2, FAK, SOS, GRB2, RACK1

② 2^nd. Rac + GTP

③ 3^rd. PAK

④ 4^th. Raf1, MEK1

⑤ 5^th. Erk1/2, MSK1/2

⑥ 6^th. 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

○ In addition, receptors with similar structures that mediate inflammatory responses form 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

○ 1^st. Fas or TNF binds to receptors.

○ 2^nd. CASP8 (caspase 8) binds with an adaptor, forming DISC.

○ 3^rd. DISC activates caspase 3.

○ 4^th. CASP3 (caspase 3) causes cell death.

④ Cell survival and inflammatory response signaling pathway

○ TNFR → TRAF2 → MEKK1/4 → MEKK4/7 → JNK → AP-1 → Inflammation and survival

○ TNFR → TRAF2 → ASK1 → MEKK4/7 → JNK → AP-1 → Inflammation and survival

○ TNFR → TRAF2 → RIP → MEKK3/6 → MAPK → Inflammation and survival

○ TNFR → TRAF2 → NIK → IKK → NF-κB → Inflammation and survival

○ TNFR → TRAF2 → RIP → IKK → NF-κB → Inflammation and survival

⑵ Toll-like receptor(TLR)

① Types of TLRs

○ TLR-1: Recognizes multiple triacyl lipopeptide.

○ TLR-2: Recognizes lipoteichoic acid. Activates innate immunity.

○ TLR-3: Recognizes dsRNA present in viruses.

○ TLR-4: Recognizes LPS (lipopolysaccharide) present in Gram-negative bacteria

○ TLR-5: Recognizes flagellin, the structural subunit of prokaryotic flagella.

○ TLR-6: Recognizes multiple diacyl lipopeptide.

○ TLR-7: Recognizes single-stranded RNA.

○ TLR-8: Recognizes small synthetic compounds and single-stranded RNA.

○ TLR-9: Recognizes unmethylated C^pG 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 into 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 into the nucleus → Type I IFN

○ TLR → TAM, TRIF → TRAF6 → NF-κB → NF-κB translocates into the nucleus.

○ TLR → TAM, TRIF → TRAF6 → MAPK → AP-1

⑶ Notch signaling

① Function: Determines cell fate, and involved in 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. When the receptor itself has a catalytic domain.

② Case 2. When a coenzyme assists.

③ In both cases, dimerization of the ECR is induced, triggering signal transduction.

⑺ AGE-RAGE

⑻ Rap1

⑼ NOD-like receptor

⑽ YAP/TAZ signaling

① TAZ signaling activates fibrosis and necroptosis.

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 transduction 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

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Chapter 6. Signal Transduction

1. Overview

2. Transduction

3. G Protein-Coupled Receptors (GPCR)