Signal transduction Study Guide

📖 Core Concepts Signal transduction – conversion of an external chemical/physical cue into a series of intracellular molecular events. Receptor – protein that detects the stimulus; can be extracellular (membrane‑spanning) or intracellular (cytoplasmic/nuclear). Ligand (first messenger) – the extracellular signal that binds a receptor (e.g., growth factor, hormone, neurotransmitter). Primary effector – the protein directly altered by the activated receptor (e.g., G protein, kinase). Second messenger – small diffusible molecule generated downstream (e.g., cAMP, IP₃, Ca²⁺, NO). Signal amplification – one activated receptor can produce thousands–millions of downstream active molecules. Feedback & feed‑forward – regulatory loops that sharpen, dampen, or sustain the signal. --- 📌 Must Remember GPCR activation: ligand → receptor conformational change → GDP→GTP exchange on Gα → Gα‑GTP + Gβγ dissociate. RTK activation: ligand → dimerization → autophosphorylation of Tyr residues → docking of SH2‑containing proteins. PLC pathway: PIP₂ → IP₃ + DAG. IP₃ → Ca²⁺ release from ER. DAG + Ca²⁺ → PKC activation. cAMP pathway: Gs‑stimulated adenylyl cyclase → ↑cAMP → PKA activation. PI3K/Akt cascade: RTK‑/GPCR‑driven PI3K → PIP₃ → Akt recruitment & activation → promotes survival/metabolism. MAPK/ERK cascade: Ras → Raf → MEK → ERK → nuclear transcription factors → cell proliferation. NO signaling: NO → soluble guanylyl cyclase → ↑cGMP → PKG activation → vasodilation. Integrin signaling: ligand binding → clustering → FAK/Src activation → downstream MAPK/PI3K pathways. TLR MyD88 vs. TRIF: MyD88 → IRAK → NF‑κB (early); TRIF → IRF3 → type I IFN (late). --- 🔄 Key Processes Ligand‑binding → Receptor activation Extracellular ligand → conformational shift (GPCR) or dimerization (RTK). Generation of second messengers GPCR‑Gs: ↑adenylyl cyclase → cAMP. GPCR‑Gq: PLCβ → IP₃ + DAG. RTK: PI3K → PIP₃; Src → STAT. Signal propagation Second messenger binds effector (PKA, PKC, CaM, guanylyl cyclase). Kinase cascades phosphorylate downstream targets. Transcriptional response Phosphorylated TFs (e.g., ERK‑activated Elk‑1, PKA‑phosphorylated CREB) enter nucleus → gene expression changes. Termination Phosphatases (PTP, PP2A) dephosphorylate kinases; GTPases hydrolyze GTP; second‑messenger degradation (PDE for cAMP, phosphodiesterases for cGMP). --- 🔍 Key Comparisons GPCR vs. RTK GPCR: 7‑TM, activates heterotrimeric G proteins → rapid, reversible. RTK: single‑pass TM, intrinsic kinase activity → autophosphorylation, creates docking sites. cAMP vs. IP₃/DAG cAMP: soluble, diffuses widely, activates PKA. IP₃/DAG: membrane‑localized; IP₃ releases Ca²⁺, DAG stays in membrane to activate PKC. Integrin signaling vs. Ligand‑gated ion channel Integrin: no intrinsic enzymatic activity; signals via associated kinases (FAK, Src). Ligand‑gated channel: directly opens pore → ion flux (e.g., Ca²⁺) acting as second messenger. MyD88‑dependent vs. TRIF‑dependent TLR signaling MyD88: fast NF‑κB activation, pro‑inflammatory cytokines. TRIF: delayed IRF3 activation, type I interferon production. --- ⚠️ Common Misunderstandings “All receptors are membrane proteins.” Intracellular (nuclear/cytoplasmic) receptors bind lipid‑soluble ligands (steroids, retinoids). “Second messengers act alone.” They usually work together (e.g., Ca²⁺ + DAG → PKC). “GPCR signaling ends with Gα‑GTP hydrolysis.” Gβγ subunits also have important downstream roles. “RTK autophosphorylation = activation of every downstream pathway.” Specific phosphotyrosine motifs recruit distinct adapters, dictating pathway choice. --- 🧠 Mental Models / Intuition “Lock‑and‑key → lever” – ligand (key) fits receptor (lock); the lock flips a lever (conformational change) that pulls a rope (G protein or kinase) to lift the downstream cascade. “Amplifier circuit” – one activated receptor can turn on many G proteins, each G protein can activate many enzymes, creating a geometric cascade (signal gain). “Domino effect” – phosphorylation of one protein (first domino) creates a binding site for the next, propagating the signal linearly (e.g., MAPK cascade). --- 🚩 Exceptions & Edge Cases Constitutively active receptors (e.g., HER2 overexpression, CXCR2 mutations) signal without ligand → oncogenesis. Lipid‑soluble ligands cross the membrane and bind cytoplasmic/nuclear receptors; they do not use second messengers. Mechanotransduction can bypass classic ligand binding; integrin clustering or stretch‑activated channels generate signals directly from force. TLR4 uniquely uses both MyD88 and TRIF pathways, providing a dual‑phase response. --- 📍 When to Use Which Identify the stimulus → if hydrophobic hormone → think intracellular/nuclear receptor. Rapid ion flux needed (neuronal synapse) → ligand‑gated ion channel. Broad metabolic response (glucose uptake, lipolysis) → cAMP‑PKA or PI3K‑Akt pathways. Growth‑factor–driven proliferation → RTK → MAPK/ERK (and possibly PI3K‑Akt). Stress/apoptosis → lipid messengers (DAG, ceramide) or NO/cGMP pathways. Mechanical cues → integrin‑FAK or YAP/TAZ pathways. --- 👀 Patterns to Recognize “Ligand → Dimerization → Autophosphorylation” → hallmark of RTKs. “GDP→GTP exchange on Gα” → indicates GPCR activation. “PIP₂ → IP₃ + DAG” → signals involvement of PLC‑β (Gq‑coupled or RTK). “Phosphotyrosine motifs + SH2 domain” → recruitment of downstream adapters (Grb2, PLCγ). “Rapid Ca²⁺ spike + PKC activation” → concurrent IP₃/DAG pathway. --- 🗂️ Exam Traps Confusing Gα vs. Gβγ functions – remember Gβγ can open ion channels independently of Gα. Assuming all GPCRs use Gs – many couple to Gi (inhibit adenylyl cyclase) or Gq (activate PLC). Mixing up second messenger degradation – PDEs break down cAMP/cGMP; phosphatases dephosphorylate proteins, not second messengers. Attributing all calcium signals to IP₃ – Ca²⁺ can also enter via voltage‑gated or ligand‑gated channels. Believing every RTK activates MAPK – some primarily signal through PI3K‑Akt or STAT pathways; pathway choice depends on docking motifs. ---