浙江大学医学院：细胞信号转导与疾病 Cell Signal Transduction and Diseases

Cell Signal Transduction and Diseases Jimin shao(邵吉民) Professor, Dept. Pathology and Pathophysiology Tel:88208209 E-mail:shaojimin@zju.edu.cn

Cell Signal Transduction and Diseases Jimin Shao (邵吉民) Professor, Dept. Pathology and Pathophysiology Tel: 88208209 E-mail: shaojimin@zju.edu.cn

1. Introduction: Cell signaling and signal transduction (1) Cell signaling (2) Types of cellular signals (3) Functions 2. Gap junction and diseases (1 Structure of gap junction (2)Function of gap junction (3)Related diseases 3. Receptor-Mediated Signal Transduction and diseases (1)Cell-surface receptors (2)Nuclear receptors B3)Regulatory mechanisms of signal transduction (4)Disorders and related diseases

1. Introduction: Cell signaling and Signal transduction (1) Cell signaling (2) Types of cellular signals (3) Functions 2. Gap junction and diseases (1) Structure of gap junction (2) Function of gap junction (3) Related diseases 3. Receptor-Mediated Signal Transduction and diseases (1) Cell-surface receptors (2) Nuclear receptors (3) Regulatory mechanisms of signal transduction (4) Disorders and related diseases

Introduction: Cell signaling and signal transduction 1. Cell Signaling (1) Direct Intercellular Communication Gap Junction magnet ◆ Gap Junction (2)Signaling by plasma-membrane bound molecules (3) Receptor-Mediated Intercellular communication Cell-Surface Receptors ◆ Nuclear Receptors SIGNALING BY PLASMA-MEMBRANE-BOUND MOLECULES SIGNALING BY SECRETED MOLECULES SIGNALING TARGET SIGNALING TARGET CELL CELL CELL CELI signaling molecu鲁 receptor molecule

Introduction: Cell signaling and Signal transduction 1. Cell Signaling (1) Direct Intercellular Communication ◆Gap Junction (2) Signaling by plasma-membrane bound molecules (3) Receptor-Mediated Intercellular communication ◆Cell-Surface Receptors ◆Nuclear Receptors Gap Junction

pes of cellular signals (1) Chemical signals Hormones, neurotransmitters, growth factors, cytokines odor molecules; ATP, active oxygen; drugs, toxins, etc 2)Physical signals Light, electronic, mechanic, UV, heat, volume, osmotic, etc

2. Types of cellular signals (1) Chemical signals Hormones, neurotransmitters, growth factors, cytokines; odor molecules; ATP, active oxygen; drugs, toxins, etc (2) Physical signals Light, electronic, mechanic, UV, heat, volume, osmotic, etc

(3) Modes for the function of endogenous signals Endocrine Act on a far away organ via blood circulation, seen in most hormones Paracrine ct on a nearby target, seen in GFs, CKs, etc Synaptic: Presynaptic to postsynaptic(neurotransmitters Autocrine Act on itself after secreted, seen in GFs, especially in tumor tissues Intracrine Act on itself before secreted, seen in nuclear receptors

Endocrine Act on a far away organ via blood circulation, seen in most hormones Paracrine Act on a nearby target, seen in GFs, CKs, etc Synaptic: Presynaptic to postsynaptic (neurotransmitters) Autocrine Act on itself after secreted, seen in GFs, especially in tumor tissues Intracrine Act on itself before secreted, seen in nuclear receptors (3) Modes for the function of endogenous signals

CAI PARACHINI SYNAPTIC chernak EMIa ng e t roet colls 050 HorN Cos larget ceft eia作m ICI ENDOCRINE Im AUTOCRINE endocrine cell 零 nood Microvesicles are membrane-enclosed extracellular vesicles shed from the plasma membrane or derived from the endosomal membrane of cells which can mediate intercellular communication through transferring the vesicular components to recipient cells

Microvesicles are membrane-enclosed extracellular vesicles shed from the plasma membrane or derived from the endosomal membrane of cells， which can mediate intercellular communication through transferring the vesicular components to recipient cells

3. Cell Signal Transduction Pathways Physiological functions Metabolism Cell cycle, growth, differentiation, and apoptosis Responses to stress 应激 --etc 热、H2C2 RTK 整合素 tho d PLC 〔与细 DAC PKB 胞外基 粘附) PKC FAK MAPKK 细胞因 A,钙调蛋白,MPK 线粒体 细胞间 CaM-K 粘附 PKA STAT冖 IAPK 钙”素 TNF-R. 转录因子转录 PSTK STAT 事 型受体 NF- B 一”核受体 DNase激活 LPS 细胞死亡 tNFa lL-β 蛋白质分解 脂溶性激素(维生素A、D和甾体徼素)

3. Cell Signal Transduction Pathways --Physiological functions --Metabolism --Cell cycle, growth, differentiation, and apoptosis --Responses to stress --etc. LPS TNF IL-1

Gap junction 1. Structure of Gap Junction Connexins are four-pass transmembrane proteins, Extracellular six of which assemble to form a channel. a connexon 12 20 different isoforms of connexins in humans and mice /tc c Intracellular Interacting plasma membranes channel 1.5 nm in diameter homomeric gap of 2-4nm connexon two connexons in composed of register forming six subunits heteromeric homotypic heterotypic open channel between adjacent cells connexins connexons intercellular channels

1. Structure of Gap Junction ⚫ Connexins are four-pass transmembrane proteins, six of which assemble to form a channel, a connexon. ⚫ ~ 20 different isoforms of connexins in humans and mice Gap junction

2. Function of Gap Junction Used by most cells in animal tissues with the exception of a few terminally differentiated cells, such as skeletal muscle cells and blood cells Allowing inorganic ions and other small water-soluble molecules to pass directly from one cell to the other thus coupling the cells both electrically and metabolically In electrically excitable cells such as nerve cells allow action potential to spread rapidly without the delay that occurs at chemical synapses The sharing of small metabolites and ions provides a mechanism for coordinating the activities of individual cells (metabolic cooperation)

• Used by most cells in animal tissues with the exception of a few terminally differentiated cells, such as skeletal muscle cells and blood cells • Allowing inorganic ions and other small water-soluble molecules to pass directly from one cell to the other, thus coupling the cells both electrically and metabolically ◆ In electrically excitable cells such as nerve cells allow action potential to spread rapidly without the delay that occurs at chemical synapses ◆ The sharing of small metabolites and ions provides a mechanism for coordinating the activities of individual cells (metabolic cooperation) 2. Function of Gap Junction

3. Gap Junction in Diseases Connexin gene mutation and diseases Congenital non-syndromatic deafness(Cx26 mutation) Congenital cataract(Cx50 mutation Axonal degeneration of peripheral nerves(CX32 mutation) Infertility of females( Cx37) Gap junction and tumor promotion Gap junction intercellular communication down-regulated Gap junction and embryogenesis embryo development(Cx43) nutrients transportation( Cx26) Others

3. Gap Junction in Diseases • Connexin gene mutation and Diseases – Congenital non-syndromatic deafness (Cx26 mutation) – Congenital cataract (Cx50 mutation) – Axonal degeneration of peripheral nerves (Cx32 mutation) – Infertility of females (Cx37) • Gap junction and tumor promotion -- Gap junction intercellular communication down-regulated • Gap junction and embryogenesis -- embryo development (Cx43) -- nutrients transportation (Cx26) • Others