Signalling Pathways IN Development and Cancer Flashcards
What are the 2 pathways invovle din cell-cell signalling
Notch
Hippo
What pathways are inovlved in larger distance
Wnt
Hedgehog
What are the notch receptors and ligands
4 Notch recepetors
5 ligands: DLL 1,3 and 4
Jagged 1/2
How are the Notch receptors synthesised
Synthesised as single precuros protein that is cleaved on the way to cell surgace by furin-like proteases
Expressed as a heterodimer; has 2 extracellular subunits and TM and cytoplasmic region
THe extracellular subunits have EGF-like repeats followed by 3 cystein LIN12/Notch repeats that prevent ligand-independent binding
How do ligands actovate Notch
2 successive proteolytic cleavages
First on the extraceullalar subunit near the TM domain by a metalloproteinase of the ADAM family
Extracellular subunit and ligand are endocytosed
Then mono-ubiquitination process follows which triggeres endocytosis of the TM Domain –> This liberates NCID which then rravels to the nucleus
How does nucelus cause transcription
NCID heterodimerises with CSL transcription factor
In the absence of Notch CSL fucntions as a transcriptional repression
NCID and CSL recuir transcription co-activators
WHat genes does notch cause transcitpion of
c-myc and CDKN
What does Nothc function in
Stem cell maintenance
Lateral signaling
Induction Signalling
Differenetiation and cell cucle arrest
What cancers in Notch implciated in
T-ALL
Breast cancer
What does Notch act as TSG
Notch deficient means that mice develop BCC
How does Nothc cause breast cancer
insertion of MMTV increase Notch 4 expression which is truncated
Notch 1 activity also increased in 50% of tumours
What is at the core of the hippo pathway
The core kinase cassette
What makes up the core kinase cassette of the hippo pathways
MST1/2 - kinase
LATS1/2 - TSG
SAV1A
MOB1A
What does the core kinase cassette repreess in the hippo ptahway
YAP/TAZ
What properties regulate the hippo pathway
Apico-basla polirty –> loss of ABCP proteins
Cell-Cell Adhesion - E cadherin can sequester it
Mechanotransduction
Contact Inhibition
What is the role of Hippo In Pathway
NF2 mutation in neurofibromatosis type II
YAP1 locus frequently amplified in cancer e.g. HCC and increasesd YAP nuclear localisation seen in cancer e.g. colon
What type of genes are Wnt and Hh in Drosophilia
Segment polarity genes
What does LOF mutaitons in Wnt cause
Tetra-amelia
What is the role of Wnt in development.homeostarsis
Invovled in patterning throughout the embrup
Essential for dorsal/ventral axis formation in the early embyro
Wnt Promotes proliferation and fiferentiation
What is Hh role in development
It is a classic morphogen Causes different cell fates at different concentration Controls midline formation Regulates L/R aassymetry in the head Regulates EMT interactions Controls digit number and polairtyh
Describe the Hh Pathway
Hh signalling binds to the Ptch1 receptor –> repression of Smo released –> allows expression and or post transclation processin oft he Gli transcription facotrs
Hh rle in cancer
Loss of Patched in BCC
Activation mutaitons of Smo found in BCC
Also pathway activation found in glioma, medulloblastoma, fibrosarcoma
What are the Notch target genes
Myc, CDKN, Hes
What abherrant Notch signalling also occurs in breast cancer
c-kit and PDGFR expressionis increased
What happens if you get MMTV insertion at notch 1
Less common
Get non-invasive papillary tumours that regress on gloand involution
What is a negative notch regulator
Notch –> aggressive mammarry carcinomas often lose numb
What other cancers is notch often mutated
Notch and pancreatic cancers
What ocurs in pacnreatic cancerts
Upregulation of notch, ligands and targets increased in pre-neoplastic incasive lesions may be an early event in pancreatic cancer
Which other pathway is there also an increase in Notch mediated signalling
Increase in TGF-alpha induced EGF signalling
What organ does Notch act as a TSG in
The skin
get an upregulation of skin differentiatoin markers i.e. Keratin 1/10
What does notch repress in the skin
Notch increases p21 and p21 can repress Wint4
How can we target notch
Anti - DLL4 - Dll4 is a notc signalling component involved in angiogenesis
Small molecule inhibitors of gamma secretase –> prevents NCID release –> targets all notch receptors shown
What has small molecule inhibitors of gamma secretase been inhibited in
Kaposis sarcoma as this overeperessed notch 1, 2 and 4 BUT bad SE Of treatment e.g. GI cytotxicity
What can YAP Promote
YAP can promote EMt
What is Hippo deregulated in
Lung and colon cancer
What are their germline mutations of hippo in
Type 2 NF
What other patways can deregulate Hippo
Wnt and TGF-B
B catenin can cause nuclear accumulation of Yap
How can we target Hippo
Target Kinases
Target Yap - Verteporfin
What is Verteporfin used for
Targeting YAP
Already used as a photosensitiser in photocoagulation therapy for the teratment of macular degerneation.
What defect do you get with Wnt 1 deletion
Midbrain defect
Discuss the structure of the Wnt Receptors
FXD and LRP5/6
has 7 TM and extracellular N terminus rich cysteine rich domain which is the primary Wnt binding site
What other condition NOT CANCER is wnt deregulated
Hereditary osteoporosis
What negatively regulates Wnt in bone
SOST –> we can give SOST inhibitors to treat hereditary osteoporosis
What else can we inhibit to treat Wnt
Porcupine inhibitors –> as porcupine acetylate Wnt
What is Hh mutated in
BCC and Gorlins syndrome
Also increased Hh Ligand in small cell lunc cnacner and pancreativ cancer
Where is Hh secreted from
IN embyronic development the celles that secrete Hh are distinct from those that have receports. Thought this may also be the case in tumours in which the stromal cells screte Hh
Ihibitors of Hh signalling
1) cyclopoamine –> inhibits Smo and succes seen in BCC
2) GANT-68 –> works downsteam of Smo and inhibits DNA binding but the precise mechanism is unknown
3) mAB to rpevent ligand binding
