Signal Transduction, Cell Death, Calcium Flashcards
GPCRs
- Types, activates which G proteins?
- Each G protein type: signaling does what generally?
- Alpha 1 (Gq), Alpha 2 (Gi), Beta (Gs)
- Gq: activates PLC –> cleaves PIP2 into DAG and IP3 –> DAG activates PKC leading to smooth m. contraction and gluconeogenesis/glycogenolysis in liver; ; IP3 opens Ca2+ channels in ER
- Gi: inhibits adenylate cyclase –> no cAMP –> smooth m. contraction
- Gs: activates adenylate cyclase –> cAMP –> inhibits MLCK (myosin light chain kinase) –> smooth m. relaxation
GPCR signaling generally
- First steps
- Termination
(1) Signal binds GPCR –> inactive G protein complex (alpha, beta, gamma) is activated (GDP to GTP in alpha subunit) –> alpha-GTP subunit goes on to activate or inactivate adenylate cyclase (Gs/Gi cascade) or PLC (Gq)
(2)
- Alpha subunit has GTPase domain –> eventually Alpha-GTP turned into Alpha-GDP, inactivating it. This is stimulated by RGS proteins (regulation of G protein signaling)
GPCR Densensitization
BARK binds GPCR-G protein (beta/gamma) complex and phophorylates –> BARR binds complex and removes from membrane
Gs signaling cascade
Signal –> GPCR –> G complex (alpha, beta, gamma)–> Alpha-GDP to Alpha-GTP –> activates adenylate cyclase –> active AC makes cAMP from ATP –> cAMP activates PKA which PPlyates downstream targets
When terminated, cAMP degraded by cAMP phosphodiesterase. Downstream targets of PKA dePPylates by PP2A
Receptor Tyrosine Kinases generally (first steps)
Signal binds RTK which dimerizes and transautophosphorylates allowing signal receptor proteins to bind (at SH2 or SH3 domains)
Activation of Ras
Active RTK —> Grb2 binds at SH2 domain –> Sos (Ras-GEF) binds to Grb2 at SH3 domain –> Sos activates Ras (Ras-GDP to GTP) –> Ras-GTP has downstream signalling
- Gerber (Grb2) comes into town (RTK). Gerber (Grb2) got Soused (Sos) with Rusty (Ras).
Ras-MAP pathway
(Active RTK —> Grb2 binds at SH2 domain –> Sos (Ras-GEF) binds to Grb2 at SH3 domain –> Sos activates Ras (Ras-GDP to GTP))
Ras-GTP PPylates Raf PPylates Mek PPylates Erk –> Erk enters nucleus and ppylates proteins and transcription factors.
- Rusty and Raffiki Make and Irk
Bad pathway
Bad pathway is bad for apoptosis (activates apoptosis inhibitor)
Active RTK ppylates PI3K –> PI3K converts PIP2 into PIP3 –> PIP3 is scaffold for PK1 and Akt –> PK1 ppylates Akt –> mTOR ppylates Akt –> active Akt dissociates from PIP3 –> Akt inactivates Bad (normally binds and inhibits apoptosis inhibitor) –> Activates apoptosis inhibitor
- PIE (PI3K) consumption makes Pippin twins (PIP2) into Pippin triplets (PIP3). This miracle is the basis on which state building by Pikes (PK1) and Akhenaten (Akt) occurs. Pikes (PK1) and Towers (mTOR) give Akhenaten (Akt) power (ppylates). Powerful Akhenaten kills Bad guys that are restraining good guys that save people (inactivates Bad which normally inhibits apoptosis inhibitor)
Insulin pathways
- Common beginning
- Pathway leading to trx of cell division genes
- Pathway leading to decreased glycogenesis and increased glucose uptake
- Termination
(1) Active RTK –> IRS1
(2) Active IRS1 binding site for Grb2 –> Sos binds to Grb2 –> Sos activates Ras –> Ras pathway
- IRS comes into town. Gerber likes the IRS. Gerber gets Soused with Rusty. Rusty and Raffiki Make and Irk. Irksomeness (Erk) attracts Elks (ELK1). Elks lead to cell division.
(3) IRS1 activates PI3K –> PI3K turns PIP2 to PIP3 –> PIP3 scaffolding for PK1 and Akt –> Akt activated by PK1 and mTOR –> Active Akt increases number of GLUT4 transporters in membrane –> Active Akt ppylates GSK3 which inactivates glycogen synthase
- IRS comes into town and stimulates production of PIE (PI3K), consumption of which makes Pippin twins (PIP2) into Pippin triplets (PIP3). Miracle on which state building by Pikes (PK1) and Akhenaten (Akt) proceeds. Pikes (PK1) and Towers (mTOR) gives Akhenaten power (ppylates).
- Powerful Akhenaten increases import of food (more GLUT4) and tells Gussy (GSK3) to stop construction of food warehouses (glycogen synthase)
(4) PTEN inactivates PIP3 preventing Akt binding.
- Ptolemy (PTEN) kills the Pippen triplets (PIP3). No miracle for Akhenaten to build state on.
JAK-STAT pathways
(1) JAK and STAT bind to active RTK –> JAK ppylates STAT –> STAT dimerizes –> STAT dimer affects gene expression
- Jack and Stat come to town. Jack energizes Stat, who spontaneously clones himself. Stat twins go into jean industry.
(2) Jack’s in town. Shakespeare also comes. Gerber likes Shakespeare and sticks with him. Gerber Soused Rusty.
Necrosis
- Is
- Hallmarks include
Passive process that results in cell death due to tissue injury. Very messy
Hallmarks include cell and organelle swelling, loss of membrane integrity and release of cellular contents including cytokines
Necroptosis
- Is
- Activated how
Is a regulated necrotic pathway that is a normal part of development and physiology. It is an alternative to apoptosis when the death signal is strong and caspases aren’t available. Same hallmarks as necrosis.
- DNA damage/viruses/some active receptors in cell membrane activates RIPK3. Eventually leads to cell lysis (MLKL involved)
Caspases
- Are
- Interact with signals how?
- Types
- Can be detected by
- Enzymes that characterize the apoptotic pathway. Cysteine proteases that target aspartate.
- By binding them with their DED or CARD domains.
- Initiator caspases (inactive monomers) and Executioner caspases (inactive dimers, activates by initiator caspases
- Caspase assay, TUNEL staining, presence of active CAD in gel electrophoresis (executioner caspases cleave iCAD and make CAD)
Extrinsic apoptosis signals
Fas, TNS-a (can both promote or inhibit apoptosis depending on receptor), TRAIL (same as TNS-a)
Bcl2 family
Family of proteins that are involved in intrinsic apoptosis pathway. Several members: Bcl2 (anti-apoptotic), BH3-containing (pro-apoptotic), BH123-containing (pro-apoptotic)
