L10 - Cell signalling in cancer

Question 1

RTKs: what are they, what is their structure, how does their activation work, what do they do, and what implications can they have in cancer?

Answer 1

Receptor tyrosine kinases

• Cytoplasmic domain - similar in all RTKs, even those not membrane-bound
• Transmembrane domain
• Ectodomain - variable, these bind to ligands

Ligand binds to them, transphosphorylation of the dimer occurs and any adaptor kinases bound

Cause downstream signalling

• Mutations that cause constitutive activation - activation independent of ligand binding
• Mutations that cause overexpression of the RTK - ligand binding activation may cause hyperactivation which is difficult to turn off

Question 2

Paracrine signalling

Answer 2

Cell-to-cell communication acting locally on neighbouring cells

Question 3

Autocrine signalling: what is it and how may it work in cancer?

Answer 3

Cell signalling to itself

Overactivation of Ras causes production of TGF-alpha which causes autocrine activation of EGF receptors causing mitogenic responses to be activated

Question 4

Src

Answer 4

Idontwannalearnthis

Question 5

RTKs: how do they have kinase activity to activate Ras and how can this process be cancer-causing?

Answer 5

• RTKs don’t act like kinases towards Ras, they activate the SH2 domain on Grbs which activate GEFs (ie son of sevenless - Sos) which exchange Ras’ GDP to GTP which activates it (direct pathway)
• They can also have an SH2 domain-containing protein activate Grb which activates Sos (less direct pathway)

If the GTPase activating protein (GAP) is blocked from activating properly (ie NF1), Ras may be constitutively activated, a potentially cancer-causing situation

Question 6

pTEN: what is it and what does it do?

Answer 6

Tumour suppressor

Dephosphorylates PIP3 into PIP2

Question 7

PI3K: what is it and what does it do?

Answer 7

Proto-oncogene

Phosphorylates PIP3 into PIP2

Question 8

pTEN and PI3K: which is the proto-oncogene and which is the tumour suppressor?

Answer 8

PI3K: Proto-oncogene as PIP3 can activate Akt which can potentially have oncogenic properties (cell survival/cycle) if dysregulated (Akt inhibits CDKIs - cell cycle promoted)

pTEN - tumour suppressor as it dephosphorylates PIP3 back into PIP2 which stops its cell cycle promoting properties

Question 9

MAPK pathway: normal vs in cancer

Answer 9

RAS activates RAFs, causing their dimerisation and autophosphorylation between dimers and other sites

Cancer - BRAF has a V600 mutation, resulting in constitutive activation without Ras activation

Question 10

Step-wise model of cancer

Answer 10

Not one single loss of function mutation is enough, a gain of function is also needed potentially through a different pathway, both occurring simultaneously may result in cancer formation