Tyrosine kinase in cancer Flashcards
How many TKs are there in the human genome?
~90
What are the two types of TKs?
Cytoplasmic and receptor TKs
what induces activation of RTKs?
oligomerisation (dimerisation etc)
What changes occur to an RTK following its activation
Following ligand binding, a conformational change induces the activation of the TK domain. This leads to transphosphorylation of the partner receptors cytoplasmic domain.
How do most cytoplasmic TKs associate with receptors that lack intrinsic TK activity
Non-covalently.
How do cytoplasmic TKs become activated.
Similar RTKs, oligomerisation induces transphosphorylation of TKs which then phosphorylate the receptor itself.
Give 5 ways in which tyrosine kinases get inappropriately activated in malignant disease
- Mutation resulting in constitutive activation or hypersensitivity
- By fusion to other proteins
- By receptor overexpression leading to reduced threshold for signalling
- By activation of upstream signalling pathways
- By autocrine production of growth factors
Give an example of a mutation resulting in constitutive activation or hypersensitivity
EGFR in lung cancer, FLT3 in AML, JAK2 in myeloproliferative neoplasms
Give an example of a fusion event to another protein that causes malignant disease
BCR-ABL in CML, EML-ALK in lung cancer
Give an example of receptor overexpression leading to a reduced threshold
EGFR, HER2 in various cancers
Give an example of upstream signalling activation pathways that lead to malignancy
B-cell receptor and subsequent BTK activation
Give an example of autocrine production of growth factors that leads to malignancy
IGF1 production by numerous tumours
How are chromosomal translocations detected?
Cytogenetics, FISH or PCR which spans the break point of the fusion.
How do chromosomal translocations induce malignancy?
Through inappropriate activation of target gene(s) or in the wrong cellular location (changes in protein localisation due to fusion may induce the activity of inappropriate pathways
Which hallmarks of cancer does TK activation mainly contribute to
Sustained proliferation and reduced sensitivity to cell death/antiproliferative signals.