Wnt Signalling Flashcards
what are three functions of effector proteins?
transcription regulation
cytoskeletal regulator
metabolic enzyme
what are the five forms of intracellular signalling?
juxtacrine, paracrine, autocrine, synaptic, endocrine
what are three major classes of receptors?
ion-channel-couple receptors
g-protein-coupled receptors
enzyme-coupled receptors
what are three downstream signal transduction components?
elements can activate or inhibit each other (often via phosphorylation- a MAPK cascade etc) secondary messengers (cAMP, PIP3 etc) intracellular signalling complexes (scaffolding proteins - SH2 etc)
what is positive feedback?
moderate or strong (strong = all or none response)
bistable system
B enhances/strengthens A
what is negative feedback?
dynamic equilibrium
B reduces A
stabilises a response
what is a biological example of feedback?
pattern formation in sea snails
have activator with positive feedback on self, activates inhibitor which inhibts activator with long range diffusion
so activator determines where pigment is on the shell
also involves hormones
how was wnt discovered?
in a screen for proto-oncogenes -> int1 (related to cancer)
in drosophila, int1 = wingless
what two PTMs does wnt have?
glycosylation
palmitoylation (increase affinity to PAM receptor)
how does wnt determine developmental patterning?
cell fate specification and axial patterning
how is wnt implicated in disease?
homeostatic levels of wnt = carry out all its purposes
too little wnt = degeneration
too much wnt = cancer
what are two proteins implicated in wnt modification and secretion?
porcupine
wntless
what is porcupone?
multipass transmembrane o-acyltransferase
in the ER of wnt producing cells
essential for wnt palmitoylation and maturation
loss of porc leads to retention of wnt in ER and loss of signal
what is wntless?
aka eveness interupted (Evi)
sorting receptor needed for wnt secretion
chaperones wnt membrane and localises to golgi, endosomes, and plasma membrane
what is the process of wnt transport?
start in golgi/ER and two routes:
- secreted on apolipoprotein and wnt loaded and transported
- wntless and wnt trafficked to MVB vesicles which contain smaller vesicles- exosomes
what happens when wnt signal reaches target cell?
binds to receptor: a seven-pass transmembrane receptor called frizzled
what is frizzled?
transmembrane receptor with cystein rich domain
binds wnt
what are two types of wnt signalling and the three subpathways?
canonical (wnt/beta-catenin)
non-canonical (wnt/pcp and wnt/ca2+)
what is beta catenin?
involved in cell adhesion and transcription regulation
binds transcription factor TCF/LEF when wnt is present
what happens in beta catenin pathway when wnt is not present?
beta catenin phosphorylated by ‘destruction complex’ leading to ubiquitination by beta-TrCP
this then targets beta-catenin for degradation by the proteosome
what is the wnt beta catenin destruction complex made of?
axin - main scaffold
apc - unknown function
cki and gsk3- serion threonine kinases
what does beta catenin pathway result in when wnt not present?
no target gene transcription
what happens during beta catenin pathway when wnt is present?
switching on of target gene transcription
wnt binds to frizzled and axin binds LRP (mediated by dishevelled)
kinases CK1 and GSK3 phosphorylate LRP, axin and APC but not beta catenin
receptor complex at membrane is called signalosome
bet catenin is not degraded
what is the feedback loop in wnt beta catnenin pathway?
tz and lrp taget genes
what happens because of LRP signalosome endocytosis?
once endosome formed signalosome forms and components of destruction complex are titrated away from beta catenin
internalisation of receptor complex in endosomes and MVBs
what are four ways wnt beta catenin signal can be inhibited?
dicckopf proteins - antagonise signalling by binding lrp
wnt inhibitory factor - antagonises signalling by binding to wnt
norrin and r-spondins- antagonises signal by binding to fz
what are three aspects of directional movement?
orientation in developing organism
orient a particular cellular structure along a particular axis
orient tissue movement
what is wnt pcp signalling pathway for?
establishment of planar cell polarity
so polarity in plane of tissue
has downstream protiens for cytoskeleton remodelling and actin remodelling
what is an example of wnt pcp pathway?
axis elongation in zebrafish embryo
how is cell polarity established?
signal from one side only
proximal or distal
what is wnt ca2+ signalling pathway?
release of calcium from intracellular stores triggers second messenger
is g protein dependent
includes PLC and PIP3 to activate PKC and CamKII which phosphorylate target genes
