cellular hypertrophy
DESCRIPTION
Cellular hypertrophy. Control of protein synthesis Endogenous Nutrient status Functional adequacy History Exogenous Nutrient availability Growth factors Space General phenomenon, muscle context. Immediate controls on protein synthesis. Substrate availability m-/t-RNA Amino acids - PowerPoint PPT PresentationTRANSCRIPT
Cellular hypertrophy
• Control of protein accretion– Endogenous
• Nutrient status• Functional adequacy• History
– Exogenous• Nutrient availability• Growth factors• Space
• Protein synthesis (translation)
• Protein degradation (autophagy)
Immediate controls on protein synthesis
• Substrate availability– m-/t-RNA– Amino acids– Phosphatidylethanolamine (ATG8/LC3)
• Catalyst availability & activity– rRNA & S6 phosphorylation– eIF2, 4– eEF1, 2
Major regulatory pathways
• Positive– Akt: mTORc, inhibit FOXO– mTORc
• Growth Factors, nutrients, hypoxia
• S6k, 4E-BP1, inhibit ULK-1
• Negative– AMPK
• AMP/ATP, calcium
• ULK-1, TSC1/2, eEF2K
– FOXO (transcription factors)• Ubiquitin ligase, glutamine synthase (autophagy)
Signal integration through mTOR
TSC2
TSC1
RAPTOR
Ragulator
RAG
Lysosome
Rheb
Rheb
RAPTOR
GTP
GTP
GDPRAGGDP
PRAS40LST8
PRAS40LST8
mTOR
mTOR
AminoAcids
Insulin (GF)
Hypoxia
ATP/AMP
ERKAkt
AMPK
GSK3
REDD
Adhesion
Akt
Signal integration through AMPK
ATP/AMP
GSK3
mTOR
eEF2K
TFEAutophagy
Genes
ProteinSynthesis
eIF2b
p70etc
eEF2
eIF2aCa2+
CaMKK
LKB1
STRADMOL25a
ATM
DNA Damage
SympatheticNS
PKA
Glucose uptakeLipolysis
Mitochondria
AMPKAMPK
folliculin
AMPKa
FNIP
Stimuli for size change
• Developmental– Strongly dependent on growth factors– Feedforward
• Functional– Overload– Endogenous factors– Feedback
• Integrative– Autocrine/paracrine factors
Linking growth stimuli to growth
• Insulin/IGF-1 (growth factors, generally)– IGF1IGF1RIRS1
Grb2SOSRasRafMEKERKMNK--|4EBP1
PI3K
• PI3K– IGF1/FAKPI3KPIP3PDK1akt
--|TSC--|RhebmTORRSKS6translational apparatus
--|4EBP--|eIF4Etranslational activity
--|eEF2K--|eEF2translational activity
--|GSK3b--|eIF2translational activity
Physical niche is important
• Adhesion/turnover– IntegrinFAKSrc/paxillin
PI3KAktmTORc-Myc
– Transcriptional targets include eIFs, eEFs, tRNA synthetases, Pol III, nucleolar proteins, 40S & 60S proteins
CTD phosphorylation, mRNA cap methylation
ERK1/2
Huang & Ingber 1999
Cells grown on different attachment areas. Yellowsynthesizing DNABluenot synthesizing DNA
Negative controls on growth
• AMPK– AMPAMPK
TSC--|mTOR--|IRS1GSK3b--|eIF2
• FOXO, esp FOXO3– Oxidative/heat stress/Ppar-g FOXO
p27Kip--|cell cycleMuRF, atroginubiquitinylationmyostatin (FOXO1)
• TGF-b– TGFRSMADapoptosis, cell cycle arrest…
Functional influences
• Muscle– Mechanical overload hypertrophy– Cell damage (creatine kinase)– Metabolite coupling (PPAR)
• Liver– Toxin overloadhypertrophy+hyperplasia– Cell damage (alanine aminotransferase)– Metabolite demand (PPAR)
• Epithelium– Competitive hypertrophy– Contact inhibition
Cell size transduction
• Mass action– Cube-square metabolite accumulation– Finite RNA/protein synthesis rates– Nucleus/cytoplasm volume (sc Cln3)– Diffusion (polar expression of Pom1)
• Contact– Cadherin--|b-catenincell cycle– Hippo/MST1/2--|Yki/Yapcell growth
Integrative control
• Mechanical demand– FAK, Ca2+, other force sensors
• Energetic demand– AMPK, GSK, Ragulator
• Net growth of cell depends on balance– Overloaded, high energy cell grows– Overloaded, starved cell atrophies– Infrequent overload is sufficient to maintain or
gain functional capacity
• mTOR is a signal integrator