Chamberlain Flashcards
how do cells transduce messages through the plasma membrane
Receptors
what are the 5 types of signaling
endocrine
paracrine
juxtacrine
intracrine
autocrine
Explain endocrine signalling
What is the signalling molecule for endocrine signalling?
sent via circulation,, targets receptors on cell in distant tissues, signalling molecules are hormones
ex: sex hormones
Explain Paracrine signalling
local signalling targets receptors on neighbouring cells, highly common
ex: Fibroblast growth factor family, insulin-like growth factor family
T/F normal cells synthesize their ligands in paracrine signalling
false
Explain juxtacrine signalling
receptor and target are embedded in plasma membrane, local signalling, cell-cell contact, GAP and tight junctions
ex: Notch, cadherins
Explain intracrine signalling
signalling within a cell, signal and receptor are in the cell
ex: some hormones, some GFs
explain Autocrine signalling
signalling via a single cell, express both receptor and target, common in cancer
ex: interleukin-1 and 2
Which signalling is common in cancers?
Autocrine, cancer can synthesize their own ligands
What are signals that cells sense
Food, integrin/cell junction signalling, hormone signalling, growth factor signalling
what links cells to ECM
integrins
why is integrin signalling important
protects cells from anoikis
what is anoikis
apoptosis due to loss of cell attachment
what is talin
recruits cell signalling components in integrin signalling, connected to beta subunit
what does talin recruit
recruits phosphorylated FAK which binds Grb2 which binds Sos, which allows Ras to go from GDP to GTP
what is the talin pathway that you should know? (slide 28)
Talin–> FAK –> Grb2 –> Sos –> Ras-GDP –> Raf –> MEK –> Erk
why are integrins important in cancer
provide mechanisms to protect against anoikis such as survival signalling (endosomes, ECM free signalling)
describe the general pathway of growth factors
Growth factor ligand –> receptors –> adaptors and enzymes –> signalling cascades –> transcription factors –> effect
What are growth factor
small peptides that interact with specific receptors, many secreted as inactive precursors, tie cells within a tissue together into a single community
What are mitogens? what are some examples? how are they different during cancer?
induce a cell to proliferation, VEGF, PDGF, EGF, always active during cancer usually only activated during ccell damage
what are the 3 groups of structures of growth factors
Single protein, homodimers, heterodimers
What are some of the different types of receptors?
G-protein coupled receptors, Nuclear receptors, Notch receptors, Patched receptor (hedgehog). receptor tyrosine kinase
what is the largest and most diverse group of membrane receptors in eukaryotes
G-protein coupled receptors
What are the six main classes of G-protein coupled receptors
A (rhodopsin-like)
B (secreting receptor family)
C (Metabotropic glutamate/pheromone)
D (Fungal mating pheromone receptors)
E (Cyclic AMP receptors)
F (Frizzled/Smoothened) *
describe canonical Wnt signalling
Wnt binds to Frizzled which then binds to Dishevelled. This then activates and binds to the axin complex. The complex is pulled apart leaving axin still bound to Dishevelled and LRP. Beta-catenin gets released from inactive GSK-3B, Wtx, and Apc. this results in beta-catenin promoting proliferation and stem cell state. Beta-catenin will go into the nucleus and activate transcription factors
Describe Non-canonical Wnt signalling
When frizzled binds to Wnt, it binds to an inactive G-protein (alpha, beta, gamma subunits), the inactive G-protein separates into alpha and beta-gamma subunits which are then activated. the alpha subunit replaces GDP for GTP and promotes PDE which inhibits cGMP. The beta-gamma subunit promotes PLC-B which cuts lipids in half, and ultimately increase PKC and calcium to activate cell signalling
What do nuclear receptors bind to
Steroid sex hormones, retinoids, vitamin D, small hydrophobic molecules,, bind to hormone repsonse elements
Which receptor is important in breast cancer?
Nuclear receptors
Describe Notch interactions with delta
when Delta and Notch interact, it signals for delta to be endocytosed and breaks apart the complex
Explain hedgehog signalling
If Hedgehog binds to patched, Gli is not cleaved and genes are induced and transcribed
If hedgehog does not bind to patched, Gli is cleaved and becomes a repressor of transcription
What are receptor tyrosine kinases, what are the 3 major domains
Extracellular domain, transmembrane domain, intracellular domain
what is transphosphorylation
receptor phosphorylates its binding partner
what are the combinations of homo and heterodimers
1-1
1-2: 2 ERBB2 doesn’t bind ligand
3-3: uses up ligand but doesn’t phosphorylate partner, doesn’t activate ligand
3-2: 2 doesn’t bind ligand, 3 doesn’t phosphorylate partner
4-4: normal
4-2: 2 doesn’t bind ligand
T/F there are multiple binding sites on EGF receptor
True
how do receptors act in a cancer cell
they’re either mutated affecting structure or overexpressed but they’re constitutively active
how do growth factors become deregulated
they become truncated which emit signals even in the absence of ligands
which receptor would fusion not work with?
insulin because its already a dimer
What are the two types of genes created from signalling cascades
immediate early genes, delayed early genes
T/F There are more tyrosine kinases than Serine/Threonine kinases
False, 90 tyrosine kinases, 429 serine/threonine kinases
what was the first tyrosine kinase discovered
Src
What’s the difference between v-Src and C-Src.
v-Src for viral Src. C-Src was the normal, cellular Src
study Src mech of action slide 66
What are the types of protein domains and what is one example for each
Modified peptide: SH2 bind to p-Tyr
Peptide: PDZ binds to carboxylic acid
Domain/Domain: PDZ binds PDZ
Phospholipid: C1 binds DAG
Nucleic Acid: PUM binds RNA
explain the yeast two hybrid system
Bait and prey are constructed from a proteome library. The library is screened for potential interactions between the bait and prey. If the interaction occurs then transcription will occur and from the results, you can see which receptors were important
what is the important MAPK signalling pathway
creates ERK1/2
what’s the important PI3K/ AKT signalling pathway
AKT –> mTORC1
What is the Akt/PKB pathway? what are the 4 effects
phosphorylation activates the Akt/PKB which then affects 4 molecules
Inhibits GSK-3B which inhibits proliferation
Promotes HIF-1a which promotes angiogenesis
inhibits bad which inhibits apoptosis
inhibits TSC2 which inhibits protein synthesis
will you ever see PIKC3A and PTEN mutations in the same cell
no usually one or the other
How mutated is p85a in cancer
not highly mutated
what are the two pathways of Ras activation
Tyrosine kinase binds to Grb2 which binds its SH3 domains to Sos which switches Ras from the inactive form to the active form
Tyrosine kinase binds Shc which binds to Grb2 which binds its SH3 domains to Sos which witches Ras on
explain the regulation of Ras
GTP hydrolysis and Ras inactivation induced by GAP
Ras activation triggered by GEF(Sos)
how is the mutant Ras signaling different from normal
loses the ability to alter between active/inactive states, GAPA doesn’t affect the mutant Ras
