Dysfunction of cell signaling and the related disease
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.
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
Receptors
Membranous receptors
Neuclear receptors (intracellular receptors)
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
GPCR Gs adenylate cyclase (AC) cAMP-PKA
Gq PLCβ → PIP2 → IP3-Ca2+; DAG-PKC
PI-3K-PKB
Tyrosine kinase receptor
IP3-Ca2+; DAG-PKC PI-3K-PKB Ras-Raf-MAPK (ERK)
Tyrosine kinase coupled receptor JAK-STAT
Serine/threonine kinase recptor TGF β-smad
Guanylyl cyclase (GC) receptor cGMP-PKG
Nuclear receptors
Steroid hormone
Thyroxine
Vitamin D
Ways to regulate target proteins
Reversible phosphorylation
Regulation mediated by G protein
Regulation of gene expression
Termination of signal transduction
Dissociation of ligand from receptors
Degradation of receptors
Convertion of GTP to GDP
Dephosphorylation
Dysfunction of cell signaling in disease
Aberrant extracellur signals in disease
Aberrant receptors in disease
Aberrant intracellular signaling
Multiple signaling aberrations in disease
Aberrant extracellur signals in disease
Type 1 diabetes mellitus insulin↓ antibody to insulin or destruction of β cells.
Central diabetes insipidus ADH ↓
Aberrant receptors in disease
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
Receptor defect
Excessve receptor activation
Hyperthyroidism TSHR activation by mutation
Autoimmune receptor disease TSH receptor antibody
Hyperthyroidism stimulatory antibody
Hypothyroidism inhibitory antibody
Aberrant intracellular signaling
cholera
Activity of GTPase↓
GTP can’t convert to GDP
Continuous Gs-cAMP-PKA activation
Secretion of chloride into the lumen↑
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
Cell proliferation, differenciation and the related disease
Cell proliferation and the related disease
Cell diffenciation and the related disease
Cell proliferation
Cell proliferation refers to the increase in the cell numbers as a result of cell growth and cell division.
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
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
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.
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
cyclinD-CDK4/6
↓
Phosphorylate pRb
↓
Release transcriptor E2F to translocate into the nucleus
↓
Promote Traget protein expression, such as cyclinE
↓
G1phase→S phase
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
Dysregulation of cell cycle and tumor
Cyclin overexpression
pRb mutation and downregulation
p16 mutation and downregulation
p53 mutation and downregulation
Cell differenciation
Cell differenciation means the process whereby relatively unspetialized cells, such as embryonic or regenerative cells, acquaire spetialized structural , functional and biochemical features.
Regulation of cell differenciation
Transcriptional regulation
Post-transcriptional regulation
Extracellular regulation
extracellular matrix
extracellular signal molecules
Dysregulation of cell differenciation and disease
Acute myeloid leukemia, AML
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)
Maitaining normal development
Maintaining homeostasis
Importance
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)
caspase
Initiator caspase 8, 9, 10
Effector caspase 3, 6, 7
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
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
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
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