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Cell signal transduction & diseases

Cell signal transduction & diseases. moon rover. Zhao Mingyao BMC. ZZU. cell signal transduction. specific response. cell. signal. Proliferation Differentiation Metabolism Function Stress Apoptosis.  or  or loss  disease. 1. Signal constitution. (3)Second messenger

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Cell signal transduction & diseases

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  1. Cell signal transduction & diseases moonrover Zhao Mingyao BMC. ZZU

  2. cell signal transduction specific response cell signal Proliferation Differentiation Metabolism Function Stress Apoptosis  or  or loss  disease

  3. 1. Signal constitution

  4. (3)Second messenger cAMP, cGMP Ca2+ DAG(1,2-diacylglycerol) NO, CO, ? ceramide, phosphocholine allosteric agent

  5. (4) Enzyme components ①Phospholipase(PL) :PLA2, C, D, SMase (sphingomyelinase) ②Phosphatidylinositol kinase:PI-3K, PI-4K, PI-5K / PTEN ③GP(Tripolymer & Small ) : GP(G) = GTPase ④Protein kinase & phosphatase:PSTK & TPK or PTK ⑤AC, GC/ cyclic nucleotidephosphodiesterase: phosphatase and tensin homolog deleted on chromosome ten (PTEN)

  6. (5) Receptor and its function 1. ionotropic ~: + neurotransmitter , ion 2. GPCR: metabolism , function modulation 3. ~ TPK: +insulin, GH 4. TPK-linking ~ : cytokine, antigen, some CAM 5. PSTK ~ : TGF-β 6. TNF ~ : apoptosis, NF-kB 7. Guanylyl Cyclase ~: vasodilation, excreting Na+ urine 8. CAM : communication between cells 9. Nuclear ~: transcription regulatory factor

  7. 2. Signal transduction pathway channel Transporter PL C Effect protein   E  E GTP ? GDP Neucler receptor DNA

  8. Major pathway of cellular signal transduction GP~ TPK~ GC (guanylyl cyclase)~ Nuclear ~

  9. (1) Signal transduction pathway introduced by GP receptor GP DG-PKC PLCβ AC IP3、Ca2+-CaK

  10. β-Rα2-R,M-R α1-R,ET-R Gsα GiGqα AC PLCβ cAMP PIP2 IP3 PKA DAG(DG) gene PKC Cori, 1947 Gilman 1994 - +  ? cGMP? Sutherland 1971 Murad 1998 Pro* glycogenolysis Edmond H. Fischer Krebs 1992 GPCR signal pathway

  11. Mechanism of GP GP(G) = GTPase GDP GTP off on + GEF Small GP (G) - GAP guanine-nucleotide exchange factor GTPase activating protein

  12. signal transduction pathway introduced by GP -R β-Rα2-R,M-R α1-R,ET-R Gi Gsα Gqα + + + -  AC PLCβ cAMP PIP2 IP3 PKA DAG(DG) Ca2+ released Target Pro phospho Targetgene transcription PKC Target Pro phospho

  13. Cholera toxin, CTX Cl-、H2O    GTP cAMP GDP CTX leads to Gsαarg201 ADP-ribosylation AC ATP

  14. Pertussis toxin, PTX    Giα PTX leads to Giα ADP-ribosylation, blocks its activation + - AC PLCβ

  15. (2) signal transduction pathway introduced by TPK Receptor tyrosine protein kinase, RTK (20 types) PTK-linking receptor

  16. 1)Receptor tyrosine protein kinase, RTK (20 types) TPK Ras-MAPK PLC-PIP2 PI3K Proliferation differentiation

  17. PI3K GF >50 kinds TPK Grb2 PLC Sos PIP2 IP3 PKB Ras DAG Ca2+ Raf PKC Target pro phosphorylation MEK Transcriptional factor phosphorylation DNA ERK

  18. Receptor Tyrosine Kinases

  19. 2)PTK-linking receptor IL、IFN、erythropoietin(most cytokine) JAK JAK PTK in Src family FAK PTK phosphorylation STAT inducing transcription regulating express gene DNA response element cellular phenotype change JAK-STAT Pathway

  20. (3) Signal transduction pathway introduced by GC

  21. Furchgott

  22. cytokines Furchgott found CO Ca2+ GTP R GC sGC NO synthase Ach-R cGMP arg PKG NO Vascular dilation ? VEC VSMC NO Vascular GC signal transduction system

  23. (4) Signal transduction pathway introduced by nuclear receptor GC, Mineralo~, gonadal H; Steroid hormon-R in cytoplasma except estrogen R; bind to HSP Thyroxine hormon-R T3,Vit D, Tretinoin; Dimer; in ? bind to pro or DNA ? -R as ligand-dependent transcription factor

  24. Crosstalk one or more components of one signal transduction pathway affect another

  25. 3. Pathophysiology of CST Etiology and pathogenesis Structure and expression change of gene (2) Abnormal function of immune (3) Secondary abnormality

  26. (1) Structure and expression change of gene signal pro ( p53 ) amount :↓or↑ function : ↓ or↑ structure(mutation) : domain; deactivated; continually activated; dominant negative effect GF-GFR: acromegaly and gigantism

  27. Hormone resistance syndrome A disease caused by target cell reducing or losing its response to the hormone, but the hormone synthesis and secretion in normal level Nephrogenic diabetes insipidus

  28. Constitutive activation Receptor hyperactivation out of control due to gene mutation, also known as the receptor gaining functional mutation

  29. (2) Abnormal function of immune Self-antibody against Signal Pro

  30. Stimulating Ab to the receptor for thyroid-stimulating hormone (TSH) Hyperthyroidism, proptosis (protrusion of the eyes globes), Graves’ disease • Blocking Ab to the TSHR • Hypothyroidism,myxedema Hashimoto’s thyroiditis

  31. (3) Secondary abnormality Blood pH Ion concentration ATP ·Pulling on single molecules : Nature ...

  32. Receptor up-regulation or down-regulation Receptor hypersensitivity or desensitization

  33. 4.Abnormal signal transduction and disease One or multiple pathways One or multiple steps

  34. (1) Insulin-resistant diabetes (type II) abnormal receptor, deficiency behind receptor Glucose -carry PTK Glycogen thynthase insulin Cellular proliferation

  35. (2)Malignant tumor Biological features hyperproliferation hypodifferentiation hypoapoptosis metastasis

  36. Cellular canceration Proto-oncogene: over-expression,mutation Tumor depressor gene:mutation, loss, low-expression DNA repair gene: mutation, loss, incorrect repair (polβ)

  37. Cellular canceration total features multifactors , multisteps, multigenes Colon cancer as a model

  38. From normal cell to cancer cell

  39. keep cell in G1 phase following specific program to differentiate to be senile to be apoptosis Tumor suppress gene negative signal :

  40. (3) Autoimmune receptor disease 1) Ab against receptor: structure change ; same antigen 2) Ab against specificity: Stimulating Ab + TSHR --- Graves disease Blocking Ab + TSHR --- Hashimoto disease Blocking Ab + nAchR---Myasthenia gravis chronic thyroiditis

  41. (4) Inflammation More cells, factors , complicated net LPS-R TNF-R IL-1R

  42. TNFa R SM sphingomyelinase SMase PK ceramide + NF- B  I B NF- B I B P65 P50 Gene transcription Cytokine, IM

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