○ 5^th. Released Ca2+ binds to calmodulin or acts as a secondary messenger to activate PKC and other proteins. DAG also influences protein phosphorylation.

○ 6^th. 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 1^st. Epinephrine (adrenaline) binds to a type of GPCR called epinephrine receptor.

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

③ 3^rd. Gαs 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 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

○ 1^st. Gαi is activated.

○ 2^nd. Acetylcholine (Ach) binding to the muscarinic receptor causes separation of the βγ subunits from the α subunit.

○ 3^rd. αi subunit inactivates adenylyl cyclase : Interaction with Gαs protein.

○ 4^th. 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

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

○ 2^nd. GPCR activates Gαs.

○ 3^rd. Gαs 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 and water efflux cause diarrhea and dehydration.

② Pertussis toxin

○ 1^st. ADP-ribose reacts with Gi, decreasing Gi activity.

○ 2^nd. Adenylyl cyclase activity increases.

○ 3^rd. Increased cAMP decreases secretion of chemical messengers in infected cells.

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

⑽ Example 5. Other examples of GPCRs.

① Brown adipose tissue norepinephrine receptor

② Transduction in liver cells

③ Olfactory nerve cells

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 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. 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 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 : Also known as ERK, responds sequentially

○ ERK1/2 : Inhibits feedback from GRB2 / SOS

⑦ 7^th. Inactive transcription factor myc becomes activated, and cyclin D is generated

⑧ 8^th. 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

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

○ 2^nd. 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.

○ 3^rd. 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 1^st. Formation of TGF-βRⅠ by binding TGF-β1 ligand and TGF-βRⅡ receptor

② 2^nd. Activation of Smad2, Smad3 by TGF-βRⅠ : Inhibited by Smad7

③ 3^rd. 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%204^th.-,%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)

① Lipophilic Hormone

○ 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 1^st. Binding of dsDNA (double-strand DNA) and cGAS (cyclic GMP-AMP synthase) enzyme

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

○ Inhibited by ENPP1 binding

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 activate

⑥ 6^th. 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

① Auditory Receptor

② Vestibular Receptor

③ Cutaneous Receptor

8. Adhesion Receptors

⑴ Type 1. Integrin(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

○ 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

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Chapter 6. Signal Transduction (signaling)

1. Overview

2. Transduction

3. G Protein-Coupled Receptors (GPCR)