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