Dysfunction of cell signaling and the related disease

1. Dysfunction of cell signaling and the related disease

2. Signal transduction Signal transduction refers to the process in which cells sense the extracellular stimuli through membranous or intracellular receptors, transduce the signals through intracellular molecules, and thus regulate the biological function of the cells.

3. Signals Chemical signals hormones, neurotransmitters, neuropeptide, cytokines, exogenous drugs, toxins Physical signals Mechanical stimuli, osmotic pressure change Intercellular contact or contact between cell and extracellular matrix

4. Receptors Membranous receptors Neuclear receptors (intracellular receptors)

5. Transmemtrane signal transduction mediated by membranous receptors Ionotropic receptor neurotransmitters G protein coupled receptor (GPCR) hormones, neurotransmitters, neuropeptide, chemokines, PGs Tyrosine kinase receptor insulin, growth factors Tyrosine kinase coupled receptor cytokines (interleukins, interferones) Serine/threonine kinase recptor TGFβ TNF/Fas receptor TNF, FasL Guanylyl cyclase (GC) receptor ANP, BNP, CNP, NO

6. Gs adenylate cyclase (AC) cAMP-PKA Gq PLCβ → PIP2 → IP3-Ca2+; DAG-PKC PI-3K-PKB GPCR IP3-Ca2+; DAG-PKC PI-3K-PKB Ras-Raf-MAPK (ERK) Tyrosine kinase receptor JAK-STAT Tyrosine kinase coupled receptor Serine/threonine kinase recptor TGF β-smad Guanylyl cyclase (GC) receptor cGMP-PKG

7. Nuclear receptors Steroid hormone Thyroxine Vitamin D

8. Ways to regulate target proteins Reversible phosphorylation Regulation mediated by G protein Regulation of gene expression

9. Termination of signal transduction Dissociation of ligand from receptors Degradation of receptors Convertion of GTP to GDP Dephosphorylation

10. Dysfunction of cell signaling in disease Aberrant extracellur signals in disease Aberrant receptors in disease Aberrant intracellular signaling Multiple signaling aberrations in disease

11. Aberrant extracellur signals in disease Type 1 diabetes mellitus insulin↓ antibody to insulin or destruction of β cells. Central diabetes insipidus ADH ↓

12. Aberrant receptors in disease Receptor defect Familial hypercholesterolaemia (FH) LDL receptor defect Nephrogenic diabetes insipidus ADH V2R defect Gs-cAMP-PKA-AQP2 Androgen insensitivity syndrome (AIS) AR defect Type 2 diabetes IR defect Excessve receptor activation Hyperthyroidism TSHR activation by mutation Autoimmune receptor disease TSH receptor antibody Hyperthyroidism stimulatory antibody Hypothyroidism inhibitory antibody

13. Aberrant intracellular signaling cholera Activity of GTPase↓ GTP can’t convert to GDP Continuous Gs-cAMP-PKA activation Secretion of chloride into the lumen↑

14. Multiple signaling aberrations in disease cancer Growth factors↑ FGF TGFα Growth factor receptors ↑ FGFR EGFR NGFR Aberrant activation of receptor EGFR Aberrant intracellular signaling Ras mutation TGFβ receptor mutation SMAD4 mutation

15. Cell proliferation, differenciation and the related disease Cell proliferation and the related disease Cell diffenciation and the related disease

16. Cell proliferation Cell proliferation refers to the increase in the cell numbers as a result of cell growth and cell division.

17. Cell cycle Cell cycle is comprised of a set of sequential phases which lasts from the end of last mitosis to the end of this mitosis. Four phases: G1 phase: presynthesis gap phase S phase: DNA synthesis phase G2 phase: postsynthesis phase M phase: mitotic phase

18. G0 phase cell Cell that is not actively dividing may be temporarily removed from the cycle by entering a resting state difined as G0 phase cell. Hepatocyte, fibroblast Terminal differenciation cell Cell that is permanently removed from the cycle is difined as terminal differenciation cell. Neutrocyte and cardiomyocyte

19. Regulation of cell cycle Cyclin CDK (cyclin dependent kinase CKI (CDK inhibitor) Cyclins refer to proteins presented in cell cycle with periodical concentration change due to synthesis and degradation.

20. Cyclin/CDK compound cyclinD-CDK4/CDK6 G1phase cyclinE-CDK2 S phase cyclinA-CDK2 G2phase cyclinB1-CDK1 M phase CKI Cip/Kip family p21, p27, p57 INK4 family p16, p15, p18, p19

21. cyclinD-CDK4/6 ↓ Phosphorylate pRb ↓ Release transcriptor E2F to translocate into the nucleus ↓ Promote Traget protein expression, such as cyclinE ↓ G1phase→S phase

22. Check point Cell cycle progression is strictly overseen by several checkpoints, which are quality controllers that monitor the condition of DNA throughout cell cycle and protect genomic integrity and the fidelity of chromosome seperation. p53 DNA damage →upregulation of p21 by p53 →arresting cell cycle →DNA repair When DNA fails to be repired, p53 initiates cell apoptosis

23. Dysregulation of cell cycle and tumor Cyclin overexpression pRb mutation and downregulation p16 mutation and downregulation p53 mutation and downregulation

24. Cell differenciation Cell differenciation means the process whereby relatively unspetialized cells, such as embryonic or regenerative cells, acquaire spetialized structural , functional and biochemical features.

25. Regulation of cell differenciation Transcriptional regulation Post-transcriptional regulation Extracellular regulation extracellular matrix extracellular signal molecules

26. Dysregulation of cell differenciation and disease Acute myeloid leukemia, AML

27. Apoptosis Apoptosis is commonly viewed as an energy-dependent process and a genetically regulated death form characterized by a series of intracellar molecular events. Programmed cell death (PCD) Importance Maitaining normal development Maintaining homeostasis

28. Characteristics Morphological characteristics chromatin condensation nuclear fragmentation plasma membrane blebbing cell shrinkage formation of apoptotic body Biochemical characteristics Activation of endonuclease degradation of DNA ladder pattern nucleosome Activation of caspase (cysteine-containing asparate-specific protease)

29. caspase Initiator caspase 8, 9, 10 Effector caspase 3, 6, 7

30. Apoptosis-related gene Fas (CD95, apo-1) death receptor Bcl-2 (B cell lymphoma/leukemia-2) the first gene found to inhibit apoptosis P53 induce apoptosis

31. Signal transduction in apoptosis Death receptor pathway Fas, TNFR-1 bingding the correspongding ligand →caspase8 →caspase3 Mitochondria pathway AIF(apoptosis inducing factor) cytochrome C (cyt C) apoptotic protease activating factor-1(Apaf-1) → caspase9 →caspase3

32. Mechanism Mitochondrial damage permeability transition pore (PTP) Oxidative stress ROS (reactive oxygen species) Calcium dyshomeostasis activation of endonuclease, calcium- dependent protease and phospholipase cross-talk

33. Apoptosis-related disease Defect in apoptosis tumors Excessive apoptosis Alzheimer disease (AD) Parkinson disease AIDS Both of above atherosclerosis excessive endothial cell apoptosis defect in SMC apoptosis