IGF! Flashcards
Basic role of IGF-2?
Major foetal growth factor
Basic role of IGF-1?
Considered more important for post natal growth
What are the three IGF receptors?
Insulin receptor, type 1 IGF receptor and type II IGF receptor. Type II can bind ligand but not transduce signal.
Structures of IR and type I IGF receptor?
Both are heterotetrameric (2 alpha and 2 beta subunits). Similar structures with TK domain particularly conserved; challenging for therapy. Two subunits synthesised as one polypeptide chain that undergoes post translational cleavage. Hetero-tetramer is stabilised by six inter-chain disulphide bonds.
Type II IGF receptor?
No intrinsic enzymatic activity and does not transmit a signal. Is a mannose-6-phosphate receptor and, after binding, IGFs are targeted to the lysosome therefore clearing them from the cellular environment which dampens the IGF signal. Binds to IGF-2 and IGF-1.
Insulin receptor A?
Splicing variant of insulin receptor that lacks 12 amino acids encoded by exon 11. This gives it higher affinity for all three ligands, at the expense of specificity.
Insulin receptor B?
Isoform that has lower affinity for all three ligands but is highly specific to insulin binding
IGFBPs?
Insulin-like growth factor binding proteins. Role unclear but bind with high affinity to IGFs, but not insulin. Circulating concentrations, bioavailibility and the biological effects of the IGFs but not insulin are modulated by IGFBPs. There are six IGFBPs - 1-5 bind to IGF-1 and IGF-2 equally, the sixth binds to IGF-2 with much greater affinity.
Structural similarities and differences of type I IGF receptor and EGFR?
Both have extracellular domains, transmembrane domains, intracellular domains with juxtamembrane domain, TK domain and signalling domain with tyrosine residues. However, EGFR has 4 EC domains (two CR domains) while type I IGF only has one.
Where are the missing 12 amino acids in the IR-A?
Situated in the receptor binding pocket; this explains why have high affinity as pocket is bigger and IGF-1 and IGF-2 are bigger than insulin.
What happens when ligand binds to type I IGF receptor or IR?
Ligands binds; induces conformational change in TK domain which activates the kinase. This leads to autophosphorylation of three tyrosine residues in the kinase domain and then phosphorylation of other receptor residues which act as substrates for the adaptor proteins which are then recruited (IRS-1, IRS-2 and Shc). These are phosphorylated then interact with the effector proteins, initiating the signal transduction cascade.
Why was IGF not recognised as oncogene?
Not implicated in viral oncogenes. In comparison, EGFR implicated in avian erythroblastosis virus; where the viral oncogene involved is ErbB which was recognised to be a mutated form of our own EGF receptor family. This method is the most long-standing, ever since Peyton Roux first demonstrated in his chickens that the Roux sarcoma virus was transforming. There was also not recognition that the IGF system could be activated by point mutation to be oncogenic, in comparison to neu models in mice. Also no specific point mutations recognised as being implicated, unlike the EGFR TK domain mutation that is prevalent in NSLC. While HER-2 has been identified as being amplified in breast cancer for three decades. Changes in IGF are more subtle and have required the advent of modern genomic medicine to recognise that type I IGF receptor is indeed amplified and can be transforming in assays, if not necessarily in immunocompromised mice.
Evidence for IGF involvement in cancer?
Molecular profiles show amplification, particularly of the Type I IGF receptor, and particularly in gastric cancer. Also increased tumour frequency in IGF-1 transgenic mice, and decreased in deficient. Also get increased IGF-signal transduction in tumour cells, IGFs stimulate proliferation in vitro and protect against cell death. ASO reduction of receptor expression induces cancer cell death, dominant negative IRS-1 reduces cancer cell growth, get reduction of IGF-induced motility by ASO to IRS-2, and inhibit tumour development by receptor antibodies. Raised type I IGFR associated with transformed cells, expression predicts breast cancer outcome. Type II is more of a TS gene. Genomic studies have been key. Also epidemiological (raised serum IGF asssociated with breat and colorectal, decreased IGFPB3 (more free IGF) with cancer, acromegaly with cancer. Imprinting also.
Imprinting in IGF?
Recognised that IGF-2 and type II IGF receptor are both imprinter, the formed paternally expressed and the latter maternally expressed. Loss of imprinting (LOI) of IGF-2 associated with childhood cancer and adult malignancies.
Strategies to inhibit IGF signalling family?
- Reduction of circulating IGFs by somatostatin analogues octreotide or pegvisomant which act on pituitary to decrease GH release.
- Use of IGFBPs to sequester IGF
- Competitively inhibit ligand
- Ligand antibodies developed
- Receptor antibodies (type I)
- Inhibit TK
- Inhibit downstream
