Cancer & Cell Cycle Flashcards
basis of signalling
first messengers (cytokines, growth factors, hormones, neurotransmitters, NO, histamines, eicosanoids, nucleotides) act on receiver cells, which synthesise secondary messengers (cyclic nucleotides & lipids)
cytokines
peptides/proteins derived from leukocytes that act to cause movement, growth or proliferation in cells by binding to cell surface receptos
dissociation constant
concentration at which 50% of receptors are occupied at equilibrium
Kd = koff/kon
ratio of dissociation rate and binding constant (specific to molecule and weight)
Ga size
39-46kDa; has major structural variation due to coding by ~20 genes
GTPase activity
a molecular clock, as conversion rate is known (kcat = 0.05sec^-1)
- can be increased by GAPs (GTPase activating proteins)
Gb size
37kDa
Gy size
8kDa
Receptor tyrosine kinase (RTK) mechanism
binding of ligand causes conformation change resulting in self-phosphorylation to create a binding site for SHC/Grb2/SOS. These activate Raf which activates MAPK phosphorylation cascade, resulting in phosphorylation of transcription factors to change gene expression
Ras GTPase superfamily
Can be activated by RTK, cytokine receptor, or the beta-gamma subunit of G proteins.
Causes MAPK phosphorylation cascade, which is facilitated by scaffold proteins.
MAPK pathway functions
mitosis, inflammatory response, differentiation, apoptosis
MAPK common activation loop
T-x-Y (Threonine - x - Tyrosine)
ERKs (TEY)
SAPKs (TPY)
p38 homologs (TGY)
Extracellular MAPK initiation
Ligand binding to RTK -> SHC/GRB2/SOS -> Ras GTP activation
-> Raf/MAPKKK -> MEK/MAPKK -> ERK -> MAPK ->
differentiation & cell division related genes
Stress MAPK initiation
Stress (UV/cytokine/heat) activate RasGTP -> MEK4 -> JNK/SAPs
= cell division stops, stress response
PAK
p21 activated kinase
SH2
domain that binds phospho-tyrosine
- present in STAT and also in Shc/Grb2/SOS complex
SH3
pro-line rich domain commonly found in cytoskeleton, allows localisation of proteins to membrane
paracrine
sender and receiver are in close proximity (tissue transmission)
juxtacrine
sender and receiver are next to each other (contact transmission)
autocrine
The same cell both secretes and receives the messenger (self transmission)
SHC
adaptor protein containing Sh2 sequence; binds to phospho-Tyr
Number of Tyrosine phosphorylated in RTKs
Tyr68
Grb2
growth factor receptor binding protein 2; an adaptor protein that binds to phosphorylated SHC protein via SH2 domain
p21Ras
subtypes of small monomeric GTP binding proteins.
Activated through guanine nucleotide exchange factor Sos and inactivated through GAP (GTPase activating protein).
Sos
son of sevenless; recruited to membrane by binding to SH3 domain of Grb2 to cause cause p21 Ras GTP exchange