信號轉導1-CST-Signal transduction

1、細胞信號轉導盧曉云盧曉云2015-2016學年研究生課程Signal transduction: first made its mark in the biological literature in the 1970s and appeared as a title word in 1979.Occurrence of the term signal transduction in papers since 1977. These figures were derived by an analysis of the papers contained within the MEDLINE da

2、tabase.2012-03-03: Pubmed 352720 papers；2013-02-23: Pubmed 380542 papers2014-02-15: Pubmed 409701 papers；2014-09-17: Pubmed 427621 papers2016-09-06: Pubmed 493796 papers 2012-032013-022014-022014-092016-09細胞信號轉導的起始：胞外第一信使HormoneCytokinesGrowth factorsNeurotransmitters 質(zhì)膜上信號的接收：受體GPCRRTKCytokine rece

3、ptorIon Channels胞漿信號的傳遞及效應物KinasePhosphataseLipid-derived signalsCyclic nucleotidesG protein轉錄調(diào)控：Nuclear receptorsTranscription factorsChromatin modificationStress response細胞功能信號：Cell cycle controlApoptosisER stress responseContent Reference book： Examine：Presentation + Review Presentation: from the

4、 4rd week, 3 people for each week Topic：One topic for each person NameMajorTutorResearch interest Duration：32 hours，8 weeks signal transduction is the process by which an extracellular signaling molecule activates a (membrane) receptor that in turn alters intracellular molecules creating a response.

5、 The ability of cells to receive and act on signals from beyond the plasma membrane is fundamental to life. This conversion of information into a chemical change, signal transduction, is a universal property of living cells.1.1 What is signal transduction? “No man is an island” and cells also do not

6、 live in isolation. Cells need receiving and processing information from the outside environment. Cells also communicate directly with one another and change their internal workings in response by way of a variety of chemical and mechanical signals. In multicellular organisms, many biological proces

7、ses require various cells to work together and to coordinate their activities. Different types of cell communicationContact-dependent signalingSecreted molecules mediated signalingautocrineparacrineendocrinejuxtacrine 近分泌近分泌 Communication between cells is mediated mainly by extracellular signal mole

8、cules.1.2 Initiation of cell SignalingHormone.Cytokines, ChemokinesNeurotransmitters and neuropeptidesGrowth factorVasoactive agentsThe natural extracellular ligands that bind and activate receptors have been called first messengers. Physical stimulation: sound, light, electronic stimulation, temper

9、ature, Chemical compound:Gaseous signal molecule: NO CO.Hydrophobic molecules:Hydrophilic molecules: Subtype of first messagers A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism.A growth factor is a

10、naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling

11、 molecules used extensively in intercellular communication.Vasoactive agents result in vasodilatation and increase in vascular permeability.Neurotransmitters are endogenous chemicals which transmit signals from a neuron to a target cell across a synapse.1.2.1 HormonesA hormone is a chemical released

12、 by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism.The level of hormone in the vicinity of a target cell is to be extremely low. Accordingly, the cell receptors must possess high affinity.The response times ranged from seconds to ho

13、urs.The peptide hormones vary considerably in size, ranging from a few amino acid to full-scale proteinsThyrotropin-releasing hormone (TRH)促甲狀腺素釋放激素3 aaFollicle stimulating hormone (FSH)卵泡刺激素, 200aaMessengers derived from amino acidsMessengerMessengerOrigin Origin targettargetMajor effectsMajor effe

14、ctsAdrenaline腎上腺素Adrenal medulla腎上腺髓質(zhì)Heart smooth muscle, liver and muscle adipose tissueIncrease in pulse rate and blood pressure contraction or dilatation, glycogenolysis lipolysisNoradrenaline去甲腎上腺素Adrenal medulla腎上腺髓質(zhì)Arteriolar smooth muscleVasoconstriction血管收縮Serotonin 血清素(5-hydroxy tryptamine)

15、plateletsArterioles and venulesVasodilatation 血管舒張 and increased vascular permeabilityA selection of hormones-Peptide hormonesMessengerMessengerOrigin Origin targettargetMajor effectsMajor effectsInsulinPancreatic b cellsMultiple tissuesGlucose uptake into cells, carbohydrate catabolism, protein syn

16、thesis, lipid synthesisGlucagon 胰高血糖素Pancreatic a cellsLiver adipose tissueGlycogenolysis lipolysisGastrin 胃泌素intestinestomachSecretion of HCl and pepsinSecretin 胰泌素Small intestinepancreasSecretion of digestive enzymeCholecystokinin 膽囊收縮素Small intestinepancreasSecretion of digestive enzymeFollicle s

17、timulating hormone (FSH)卵泡刺激素Anterior pituitary垂體前葉Oocyte/ovarianFollicles ovarianfolliclesGrowth oestrogen synthesisLuteinizing hormone (LH) 促黃體激素Anterior pituitaryOocyte/ovarianmaturation oestrogen and progesterone (黃體激素) synthesisThyroid stimulating hormone (TSH)Anterior pituitarythyroidGeneratio

18、n and release of thyroid hormonesOxytocin 催產(chǎn)素Posterior pituitaryUterine smooth muscle, milk ductsDilation of the cervix, milk ejection1.2.2 Growth factorsA growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Cells have

19、specific high affinity receptors for growth factors.The effects of growth factors, unlike those for hormones, may last for days.The growth factors vary in size, ranging from insulin 5.7kDa and EGF 6kDa to transferrin 78kDaThe effects of growth factors are short range, generally influencing the growt

20、h and function of neighboring cells.MessengerMessengerOrigin Origin targettargetMajor effectsMajor effectsEpidermal growth factor (EGF)Multiple cell typesEpidermal and other cellsgrowthSomatotropin 生長激素Anterior pituitaryLiverProduction of somatomedins 生長調(diào)節(jié)素Insulin-like growth factor 1, 2 (IGF1, 2)li

21、verBone, muscle and other cellsgrowthTransforming growth factor b (TGFb) Multiple locationsmultipleGrowth control1.2.3 Cytokines Cytokines are any of a number of substances that are secreted by glial cells of the nervous system and specific cells of the immune system which carry signals locally betw

22、een cells, and thus have an effect on other cells. They are a category of signaling molecules that are used extensively in cellular communication. They are proteins, peptides, or glycoproteins. The term cytokine encompasses a large and diverse family of polypeptide regulators that are produced widel

23、y throughout the body by cells of diverse embryological origin.Cytokines include the growth factors, along with such molecules as the interferon, tumor necrosis factor, and interleukins, granulocyte-monocyte colony stimulating factor and many others.Chemokines are a family of small cytokines, or pro

24、teins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines. 1.2.4 Neurotransmittersacetylcholine (ACh)dopamine (DA)norepinephrine (noradrenaline) Amino acidsGlutamate glycine-aminobutyric acid (GABA), epi

25、nephrine (adrenaline)serotonin (SE, 5-HT)nitric oxideTyrosine or tryptophan-derived and monoamineshistamineNeurotransmitters are endogenous chemicals which transmit signals from a neuron to a target cell across a synapse1.2.4 NeurotransmittersNeuropeptides are small protein-like molecules used by ne

26、urons to communicate with each other.Enkephalin 腦啡肽Met-enkephalin: Tyr-Gly-Gly-Phe-Met.Leu-enkephalin: Tyr-Gly-Gly-Phe-Leu.Somatostatin 生長激素抑制素Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu MetSubstance P1.2.5 Hormones with intracellular receptorsHydrophobic compounds that are able to cross the plasma memb

27、rane of cells and then interact with receptors that are intracellular. The hormone-bound receptors then bind to DNA and regulate the expression of particular proteins.Glucocorticoid receptorGlycogen synthesis睪酮雌二醇孕酮,黃體酮糖皮質(zhì)激素The function of first messengers can be much overlap. The coenzyme ATP and t

28、he cellular metabolite glutamate are neurotransmitters when they are secreted at synapses. The gut hormones gastrin (胃泌素), cholecystokinin (膽囊收縮素) and secretin (腸促胰液素) are also present in the central nervous system, where they have diverse functions as neuromodulators (influencing the release of oth

29、er neurotransmitters). TGFb also acts as a chemoattractant and as a growth inhibitor. Insulin acts not only to regulate glucose metabolism, but also as a growth factor and a regulator of food intake. Thrombin (凝血酶) is a growth factor but is also involved in blood clotting as and activator of platele

30、t function.Oxytocin 催產(chǎn)素Generated in the brain of both mails and females.Have the actions of both hormones and neuromodulators.A regulator of uterine smooth muscle contraction and milk ejectionA regulator of emotional states, enhancing trust and bonding between pairs of individuals. “Cuddle hormone”D

31、amasio A. Brain trust. Nature, 2005, 435: 571-572.Kosfeld M, et al. Oxytocin increases trust in humans. Nature, 2005, 435: 673-676.Larry J Young. Being Human: Love: Neuroscience reveals all. Nature 2009, 457: 1481.3 Receptors Extracellular signaling molecules are usually, but not always, recognized

32、by specific receptors that are present on the surface of the responding cell. Ion Channel-linked Receptors Receptor Enzymes G ProteinCoupled Receptors Various small hydrophobic signal molecules diffuse directly across the plasma membrane of target cells and bind to intracellular receptors that are g

33、ene regulatory proteins.1.3 Receptors1.4 General mechanisms for signal transduction蛋白質(zhì)磷酸化與去磷酸化各種離子：如Ca2+脂類或環(huán)核苷酸第二信使G蛋白細胞骨架轉錄因子核受體染色質(zhì)修飾轉錄及翻譯后調(diào)控1.5 Seconds messengers：general propertiesThe binding of ligands 配體 (“first messengers”) to many cell surface receptors leads to a short-lived increase (or dec

34、rease) in the concentration of certain low-molecular-weight intracellular signaling molecules termed second messengers.Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus.These intracellular messengers

35、 have some properties in common: They can be synthesized/released and broken down again in specific reactions by enzymes or ion channels. Some (like Ca 2+) can be stored in special organelles and quickly released when needed. Their production/release and destruction can be localized, enabling the ce

36、ll to limit space and time of signal activity.1.5 Seconds messengers: classificationThere are three basic types of secondary messenger molecules: Hydrophobic molecules: like diacylglycerol (二酰甘油), and phosphatidylinositols (磷脂酰肌醇), which are membrane-associated and diffuse from the plasma membrane i

37、nto the intermembrane space where they can reach and regulate membrane-associated effector proteins.1.2.6 Seconds messengers Hydrophilic molecules: like cAMP, cGMP, IP3, and Ca2+, that are located within the cytosol. Gases: nitric oxide (NO) and carbon monoxide (CO), which can diffuse both through c

38、ytosol and across cellular membranes.1.5 Seconds messengers: functions The elevated intracellular concentration of one or more second messengers triggers a rapid alteration in the activity of one or more enzymes or non-enzymatic proteins. In muscle, a signal induced rise in cytosolic Ca 2+ triggers

39、contraction; A similar increase in Ca 2+ induces exocytosis of secretory vesicles in endocrine cells and of neurotransmitter-containing vesicles in nerve cells. Similarly, a rise in cAMP induces various changes in cell metabolism that differ in different types of human cells. 1.6 Molecular switch pr

40、otein In addition to cell-surface receptors and second messengers, two types of intracellular signaling proteins that act as molecular switchesmolecular switches. Protein PhosphoralytionAnd Dephoralytion GTPase Switch Proteins1.6 Molecular switch proteinGTPase Switch Proteins: These guanine nucleoti

41、debinding proteins are turned “on” when bound to GTP and turned “off” when bound to GDP. The intrinsic GTPase activity of the switch proteins then hydrolyzes the bound GTP to GDP and Pi, thus changing the conformation from the active form back to the inactive form.1.6 Molecular switch proteinProtein

42、 Kinases and Phosphatases Activation of all cellsurface receptors leads directly or indirectly to changes in protein phosphorylation through the activation of protein kinases or protein phosphatases. Each protein kinase phosphorylates specific residues in a set of target proteins whose patterns of e

43、xpression generally differ in different cell types. Many proteins are substrates for multiple kinases, and each phosphorylation on a different amino acid, modifies the activity of a particular target protein in different ways, some activating its function, others inhibiting it.The activity of all pr

44、otein kinases is opposed by the activity of protein phosphatases1.7 Speed of signal transduction The speed of a response to an extracellular signal depends not only on the mechanism of signal delivery but also on the nature of the target cells response. Certain types of signaled responses, such as i

45、ncreased cell growth and division, involve changes in gene expression and the synthesis of new proteins; they therefore occur slowly, often starting after an hour or more. Other responses such as changes in cell movement, secretion, or metabolism need not involve changes in gene transcription and th

46、erefore occur much more quickly, often starting in seconds or minutes1.8 Composition of signal transduction system The intracellular signaling proteins help relay the signal into the cell by either generating small intracellular mediators or activating the next signaling or effector protein in the p

47、athway, which form a functional network as it spreads the signals influence through the cell. A signal triggers assembly of a signaling complex Intracellular signaling complexes enhance the speed, efficiency, and specificity of the response.1.8 Composition of signal transduction systemThe assembly o

48、f such signaling complexes depends on various highly conserved, small interaction domains, which are found in many intracellular signaling proteins and mediate interactions between them.1.8 Composition of signal transduction system Src homology 2 (SH2) domains and phosphotyrosine-binding (PTB) domai

49、ns bind to phosphorylated tyrosines on a particular protein. Src homology 3 (SH3) domains bind to short proline-rich amino acid sequences. Some pleckstrin homology (PH) domains bind to the charged head groups of specific phosphoinositides.PH domainPleckstrin homology domain (PH domain) is a protein

50、domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.This domain can bind Phosphatidylinositol lipids within biological membranes (such as PIP3 and PIP2), and proteins such as the -subunits of heter

51、otrimeric G proteins, and protein kinase C. Through these interactions, PH domains play a role in recruiting proteins to different membranes, thus targeting them to appropriate cellular compartments or enabling them to interact with other components of the signal transduction pathways.Ferguson, KM.

52、et al. (1995) Cell. 83(6): 1037-46.PH domainPH domain proteinSpecific Phosphoinositide Ligand Phospholipase C ; mSos1; RasGAP; Tsk, pleckstrinPI-4,5-P2Btk Tyr Kinase; Grp1; RasGAP; Akt/PKBPI-3,4,5-P3Akt/PKB; DAPP1; TAPP1PI-3,4-P2SH2 domainThe SH2 (Src Homology 2) domain is a structurally conserved p

53、rotein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. Its presence on a protein helps that protein find its way to another protein by recognizing phosphorylated tyrosine on the other protein.Its length is approximately 100 amino acids long an

54、d it is found within 115 human proteins. Regarding its structure, it contains 2 alpha helices and 7 beta strands. Research has shown that it has a high affinity to phosphorylated tyrosine residues and it is known to identify a sequence of 3-6 amino acids within a peptide motif.Waksman, G. et al. (19

55、92) Nature. 358(6388): 646-53.SH2 domainSH3 DomainSrc-homology 3 (SH3) domains generally bind to Pro-rich peptides that form a left-handed polyPro type II helix, with the minimal consensus Pro-X-X-Pro. Each Pro is usually preceded by an aliphatic residue. Each of these aliphatic-Pro pairs binds to a

56、 hydrophobic pocket on the SH3 domain.Nguyen, JT. et al. (1998) Science. 282(5396): 2088-92.SH3 domain proteinBinding partner SH3 Domain Binding Site Src tyrosine kinasep85 subunit of PI 3-kinaseRPLPVAP Class I N-terminal to C-terminal binding sitCrk adaptor proteinC3G guanidine nucleotide exchanger

57、PPPALPPKKR Class II C-terminal to N-terminal binding siteFYB (FYN binding protein)SKAP55 Adaptor protein RKGDYASY unconventionalPex13p (integral peroxisomal membrane protein)Pex5p - PTS1 receptorWXXQF unconventionalA C2 domain is a protein structural domain involved in targeting proteins to cell mem

58、branes. The C2 domain is thought to be involved in calcium-dependent phospholipid binding and in membrane targeting processes such as subcellular localisation.C2 DomainEF-hand DomainThe EF-hand motif contains approximately 40 residues and is involved in binding intracellular calcium. EF-hand domains

59、 are often found in single or multiple pairs, giving rise to various structural/functional variations in proteins containing EF-hand motifs. Proteins containing EF-hands can be grouped into two functional categories - regulatory or structural. Binding of calcium to regulatory EF hand domain-containi

60、ng proteins induces a conformational change, which is transmitted to their target proteins, often catalyzing enzymatic reactions. In contrast, binding of calcium to structural EF-hand domain-containing proteins does not induce a significant conformational change. Structural EF-hand domains seem to p