Exam 3 - Cell Signaling Slides Flashcards
To ACE Exam 3!!
What types of cell signaling are there?
- Autocrine (Cell produces signal and has receptor for it)
- Paracrine (Synaptic Transmission: cell makes signal for a receptor on other cell)
- Endocrine (Insulin from Pancreas: signal travels through blood stream)
What are the major signaling pathways?
- Glucocorticoid signaling
- Growth factor signaling
- G-protein coupled receptors (GPCRs)
- Insulin signaling
- Apotosis
What are the basics about glucocorticoid signaling?
- Stress hormone
- Nonpolar = hydrophobic
- Localized in cytosol
- Can cross membrane freely
What are some examples of glucocorticoid signaling?
Estrogen, Hydrophobic molecules
What are the steps for glucocorticoid signaling?
- Steroid hormone (transcription factor) enters cytoplasm.
- Binds to [receptor + Hsp90] chaperone complex causing Hsp90 to dissociate.
- Receptor now has exposed NLS (nuclear localization signal) sending the signal/receptor into the nucleus.
- Signal/Receptor complex dimerizes and attaches to a GRE sequence to regulate gene expression with the help of SWI/SNF BRG1 complex (DNA remodeling).
What are the basics of EGF proteins?
- Epidermal Growth Factor: Tell cell to grow and divide
2. Cannot cross membranes, need receptors.
What type of receptor is used for EGF?
Receptor protein-tyrosine kinase (RTK)
What are the steps for EGF signaling?
- EGF (ligand) binds to receptor causing receptor dimerization.
- Trans-Autophosphorylation occurs on tyrosine residues (phosphorylate each other).
- Phosphotyrosines recruit SH2 domain-containing proteins Grb 2.
- Grb 2 (adaptor) has SH3 domain and interacts with SOS (a Guanine nucleotide exchange factor (GEF))
- GEF (SOS) then activates Ras (G-protein) by promoting dissociation of GDP from Ras causing GTP to bind.
What is the protein responsible for turning off Ras?
GAP (Ras-GDP)
What is the protein responsible for turning on Ras?
GEF (Ras-GTP)
Describe the function of H-Ras, K-Ras, N-Ras.
Relay signals from RTKs
Describe the function of Rheb (Ras family).
Activates mTOR to stimulate cell growth
Describe the function of Rep1 (Ras family).
Activated by a cyclic-AMP-dependent GEF; influences cell adhesion by activating integrins.
Describe the function of Rho, Rac, Cdc42 (Rho family).
Relay signals from surface receptors to the cytoskeleton and elsewhere.
Describe the function of ARF1-ARF6 (ARF family).
Regulate assembly of protein coats on intracellular vesicles.
What are the steps for the MAPKs (Mitogen Activated Protein Kinases) pathway?
- After Ras is activated, Raf-1 (MAPKKK) interacts with Mek (MAPKK).
- Mek (MAPKK) interacts with MAPK (ERK).
- MAPK (ERK) transmits a signal from cytosol to nucleus.
What are the steps for the Serum response factor (SRF) and TCF pathway?
- After ERK is phosphorylated and enters the nucleus, it induces phosphorylation of TCF.
- Phosphorylated TCF binds to SRF and this complex increases expression of early response genes such as C-Fos and C-Jun.
- Bound together Fos and Jun are phosphorylated and form AP-1 complex, which leads to increased expression of delayed response genes.
- These delayed response genes are things like cyclins and CDKs, which are the engine for driving cell growth and division.
C-Fos and C-Jun are what type of genes and when does it increase mRNA (levels) expression?
Early-response genes and increase expressions of mRNA levels ~ 1 hour mark after addition of serum.
Cell proliferation factors (Cyclins and CDKs) are what types of genes and when doest it increase mRNA (levels) expression?
Delayed-response genes and increase expressions of mRNA levels at ~ 3 hours after addition of serum.
What is epinephrine produced from and what is it used for?
Tyrosine and induces the fight or flight reaction.
Explain the steps to the Epinephrine GPCR pathway.
- Tyrosine binds to Epinephrine receptor.
- Causes G-protein to bind to receptor.
- GDP is exchanged for GTP.
- G-alpha subunit with GTP now binds to effector protein.
- Activated effector adenylyl cyclase makes cAMP (2nd messenger).
- cAMP activates PKA (2 regulatory subunits and 2 catalytic subunits) by binding to 2 regulatory subunits causing catalytic subunits to dissociate.
- Induces phosphorylation of enzymes (inhibits glycogen synthesis, and activates glycogen breakdown)
- Also causes phosphorylation of transcription factors to increase glucose synthesis.
- All of which increase [glucose]. (more glucose helps with stress response in brain/muscles)
Describe the steps for the GPCR pathway involving PLC.
- Ligand binds to receptor.
- G-protein binds to receptor and G-alpha subunit is bound with GTP.
- Effector protein phospholipase (PLC) is activated.
- PLC cleaves PI(4,5)P2 (cleaves 4’ and 5’ OH) = PIP2 into IP3 (inositol 1,4,5 trisphosphate and DAG (diacylglycerol)
5.
PLC cleaves what?
Phosphate + head group
PLA1 and 2 cleaves what?
Fatty acid tail off glycerol
What is the effect of IP3?
After binding to IP3 receptor (ligand gated Ca2+ channel), induces the release of Ca2+ into the cytosol.
- [Ca2+] high in ER, LOW in cytosol.
What is the effect of DAG?
Activates PKC
What are the steps for insulin signaling?
- Blood glucose increases
- Insulin released
- Insulin binds to alpha chain receptors and triggers trans-autophophorylation (RTKs) beta chain
- IRS (Insulin receptor substrate) has PTB domain that binds to phosphate on RTK.
- IRS acts as docking station for Grb2 -> SOS -> Ras-GTP and PI3K (2 subunits with SH2 domains)
- PI3K phosphorylates 3’ OH from PI(4,5)P2 into PIP3
- PDK1 has PH domain that binds to PIP3
- Bound PDK1 activates PKB.
- Activated PKB induces protein synthesis, glucose uptake, and glycogen synthesis.
Low glucose
No insulin -> no glucose uptake
High glucose
Insulin released -> glucose uptake
GLUT 4
Facilitates glucose uptake (receptor)
Obesity leads to what?
Excess fat -> inhibition of insulin signaling + resistance
What are the steps for when insulin is present?
- Insulin -> IR -> IRS-1 -> P13K -> PDK1 -> PKB -> release of GLUT4 from cytoplasmic vesicle.
- Glucose binds to GLUT4 and is transferred inside cell.
What are the steps for extrinsic apoptosis?
- TNF (Tumor necrosis factor) binds to TNFR1 (receptor) and activates Death domains (adaptors).
- Domains pull in FADD and TRADD -> procaspase-8
- Initiator caspase-8 formed (protease)
- Executioner procaspases (inactive) formed
- Executioner caspase cleaves target for apoptosis.
What are the steps for intrinsic apoptosis?
- Internal cellular damage
- Activation of proapoptotic BH3-only protein and subsequent activation of Bak or Bax
- Bax channel/pore formed on surface of mitochondria
- Release of cytochrome c through pore (electron transport and cell killer)
- Apoptosome complex formed (Apaf-1 + cytochrome c + caspase 9) all recruited by cytochrome c.
- Apoptosome cleaves executioner procaspases into caspase.
- Apoptosis of targets.
