IGF signalling Flashcards
What are the IGF family proteins involved in, within normal cells?
The IGF proteins are involved in growth stimulation, wound healing, differentiation, cell survival, etc. Their role is therefore extremely important for maintaing survival.
What are the 3 ligands of IGF family
Insulin, IGF-1 and IGF-2
How is insulin processed?
Insuling processing involved removal of the signal sequence, cleavage of proprotein, removal of the C peptide and assembly of the two chains (insulin has 2 chains).
How is insulin processed in comparison to IGF-1 and IGF-2?
IGF-1 and IGF-2 are both single chain. They both retain their C and D domains therefore these are not removed during processing, unlike insulin.
What receptors can each ligand bind to?
- Insulin binds to insulin receptor.
- IGF-1 and IGF-2 both bind to type 1 IGF receptor.
- Type 2 IGF receptor binds IGF-1 and IGF-2 ligands, however it does not produce a response
What are the two isoforms of insulin receptor?
Isoform A and Isoform B. Isoform A is shorter, therefore causes a higher affinity to IGF-1 and IGF-2, over insulin.
What are insulin-like growth factor binding proteins?
IGFBPs exist to bind to IGFs and limit the availability of the ligands. However, they do not bind insulin. IGFBP1-5 interact with IGF-1 and IGF-2 equally, however IGFBP3 acts differently; it associates with an acid-labile subunit which binds to circulating IGF-1 and IGF-2, prolonging serum half-life. The IGFs bind at the carboxy and amino termini of the IGFBPs.
What occurs when the IGF family proteins bind to their receptor?
Interaction with the ligand induces a conformational change, then intrinsic kinase activity via phosphorylation of 3 tyrosine residues. Phosphorylation of the activation segment causes an active tyrosine kinase domain, allowing phosphorylation of adaptor proteins IRS-1, IRS-2 and Shc. Effector proteins interact with the phosphorylated adaptor proteins, and the signal transduction cascade is initiated regulating gene expression, protein synthesis, glycolysis, and cell proliferation/survival. Signal attenuation must occur via receptor internalisation and degradation.
What cancers are associated with IGF signalling pathways?
Increased IGF serum levels are associated with increased risk of breast cancer and colorectal cancer. Importantly, a decreased level of IGFBP3 is associated with an increased risk of cancer.
Why is loss of imprinting an issue with IGF-2 gene?
Imprinting is when different alleles of a gene are expressed to different levels depending on whether they are inherited from the mother or the father. Loss of imprinting (hypomethylation) of IGF-2 gene promotes some cancers due to increased transcription.
What is cyclolignan PPP and how does it work?
Cyclolignan PPP is a small molecule inhibitor produced to prevent binding of the ligand to the receptor to inhibit receptor autophosphorylation.
How successful was cyclolignan PPP?
Tumour size returned to normal after 15 days in patients receiving cyclolignan PPP, in comparison to control which increased to 800mm cubed.
What is the issue with BMS-754807 therapeutic?
This is a small molecule inhibitor which targets IGFR and insulin receptor. It has gone far in clinical trials (currently at phase II) however as it acts on the insulin receptor, the detrimental effects on glucose homeostasis are unknown.
Discuss figitumumab success and its therapeutic action.
Figitumumab is a humanised monoclonal antibody that was in phase II/III clinical trials used for breast, NSCLC, and prostate. It is highly specific for the type 1 IGFR and was initially being used in combination with paclitaxel and carboplatin for lung cancer. However, in phase III there were reports of deaths and adverse events, therefore the trial was discontinued. Patient stratification allowed an improved effect - when profiling tumour types it was found that sarcoma types responded better.
Discuss novel treatments currently being trialled to target IGF signalling.
Currently, a trial is recruiting participants for the combination therapy of exemestane and everolimus, with or without BI-836845. This trial is looking at breast cancer. Data now suggests that oestrogen potentiates IGF signalling, therefore targeting both IGF and oestrogen will improve treatment response. Combining with mTOR inhibitors targets another arm of the pathway activation.
