Signalling Pathways IN Development and Cancer Flashcards by Jacob Lewis

What are the 2 pathways invovle din cell-cell signalling

Notch

Hippo

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What pathways are inovlved in larger distance

Wnt

Hedgehog

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What are the notch receptors and ligands

4 Notch recepetors
5 ligands: DLL 1,3 and 4
Jagged 1/2

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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

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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

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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

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WHat genes does notch cause transcitpion of

c-myc and CDKN

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What does Nothc function in

Stem cell maintenance
Lateral signaling
Induction Signalling
Differenetiation and cell cucle arrest

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What cancers in Notch implciated in

T-ALL

Breast cancer

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What does Notch act as TSG

Notch deficient means that mice develop BCC

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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

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What is at the core of the hippo pathway

The core kinase cassette

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What makes up the core kinase cassette of the hippo pathways

MST1/2 - kinase
LATS1/2 - TSG
SAV1A
MOB1A

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What does the core kinase cassette repreess in the hippo ptahway

YAP/TAZ

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What properties regulate the hippo pathway

Apico-basla polirty –> loss of ABCP proteins
Cell-Cell Adhesion - E cadherin can sequester it
Mechanotransduction
Contact Inhibition

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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

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What type of genes are Wnt and Hh in Drosophilia

Segment polarity genes

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What does LOF mutaitons in Wnt cause

Tetra-amelia

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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