Yokomori 3 Flashcards
Briefly describe activation of tyosine kinase receptors.
1) Binding of signal molecule
2) Dimerization and autophosporylation of receptors
3) Kinase activity stimulated by cross phosphorylation between receptors
4) Phosphorylated sites act as binding sites for other proteins
What ligands are common for receptor tyrosine kinases and Ras? What do they mediate?
ligand: peptide growth hormone
Mediate cell growth and differentiation
What are the general characteristics of a receptor tyrosine kinase?
1) extracellular and cytosol component (tyrosine kinase is on cytosol side)
2) usually has “GF” in name (ie. EGF, IGF, NGF, FGF, etc.)
Briefly describe Src tyrosine kinase.
1) first nonreceptor tyrosine kinase discovered
2) SH2 and SH3 domain, SH2 is the one that recognizes phosphorylated tyrosine (know this about SH2)
3) mutation associated with cancer
Briefly describe Ras
Small GTPases regulate many aspects of grwoth, differentiation, and migration in response to extracellular signals.
Super family contains Rho/Rac, Rab, and Ran.
- Signals transmitted from tyrosine kinases to serine/threonine kinases which then go to cell nucleus.
- Ras mutation involved in 20-30% of cancers, big oncogene
Briefly describe receptor tyrosine kinase and Ras activation.
1) Binding of ligand cause dimerzation and autophosporylation of tyrosine residues
2) Causes binding of GRB2 to phosorylated tyrosine. Sos binds to GRB2 which binds to the inactive Ras (inactive bound to Ras)
3) GTP binds to Ras and becomes active, causing it to dissociate from Sos (like G-alpha)
Briefly describe Ras GTPase activity.
1) Inactive Ras bound to GDP
2) Guanine nucleotide exchange factors (GEF; also called Sos) causes releases of GDP
3) High concentration of GTP results in GTP binding and activated Ras
4) GTPase activated proteins (GAP) stimulates GTPase activity of Ras causing GTP -> GDP hydroylysis; resulting in deactivation of the GTPase
Ras GTPase is normally SLOW. needs GAP for efficiency.
What is the downstream target of Ras?
Ras -> MAP kinase kinase kinase (Raf) -> MAP kinase kinase (Mek) -> Map kinase (Erk); this goes on to activate pathways such as protein activity and gene expression.
Ras activates MAP kinase serine/threonin phosphorylation.
How does MAPK regulate transcription in nucleus?
1) RTK activates Ras
2) Ras activates MAPK
3) MAPK enters nucleus and phosphorylates TCF and SRF (serum response factor)
4) This activates SRE (serum response element); results in gene transcription
What class of syndromes result from Ras pathway mutation?
Neuro-cardio-facial-cutaneous (NCFC) syndromes
-Ras pathway is important for cognition, growth, and development
Remember Ras also involved in oncogenesis
In addition to Ras, RTKs also activate?
RTKs -> Ras -> MapK
alternatively: RTKs + Ras -> PI3k
What does PI 3-kinase do?
Phosphorylates inositol phospholipids (phosphorylates lipids) which can then signal other pathways
Describe how PI 3-kinase promotes cell survival. What regulates this pathway?
1) PI 3-kinase activated by RTK or Ras-GTP
2) Phophorylates inositol phospholipid (PI)
3) PKB binds to PI and becomes activated
4) This phosphorylated PKB now activates an apoptosis inibitory protein RESULTING in inhibition of apoptosis
- Regulated by PTEN which is antagonist (inhibitor) of PI 3-kinase, removes phosphates from PI; terminates signal by PI 3-kinase. PTEN is phosphatase. No PTEN means no apoptosis -> cancer (tumor suppressor)
How do insulin receptors work?
1) Insulin receptor is dimer, binding of insulin activates the RTK
2) IRS-tyr is phosphorylated (insulin receptor substrates)
3) Phosphorylated IRS-tyr goes on to carry on activity of insulin (activation of PKB, glucose uptake, etc.)
What is the JAK STAT pathway important for?
-Cytokine signaling
