Insulin-like growth factor II: complexity of biosynthesis and receptor binding.
Insulin-like growth factor II (IGF-II) belongs to the insulin family of peptides and acts as a growth factor in many fetal tissues and tumors. The gene expression of IGF-II is initiated at three different promoters which gives rise to multiple transcripts. In a human rhabdomyosarcoma cell line IN 157 IGF-II mRNAs of 6.0-kb, 4.8-kb, and 4.2-kb are present. Fractionation of cellular extracts on sucrose gradients and Northern blot analysis showed that only the 4.8-kb mRNA was associated with polysomes, whereas the other transcripts cosedimented with monosomal particles. This suggests that only the 4.8-kb mRNA is translated to IGF-II. The cell line secretes two forms of immunoreactive and bioactive IGF-II to the medium of molecular size 10 kd and 7.5 kd which may be involved in autocrine control of cell growth. IGF-II binds to two receptors on the surface of many cell types: the IGF-I receptor and the mannose-6-phosphate (Man-6-P)/IGF-II receptor. There is consensus that the cellular effects of IGF-II are mediated by the IGF-I receptor via activation of its intrinsic tyrosine kinase. The Man-6-P/IGF-II receptor is involved in endocytosis of lysosomal enzymes and IGF-II. In selected cell types, however, Man-6-P induces cellular responses. We have studied rat brain neuronal precursor cells where Man-6-P acted as a mitogen suggesting that phosphomannosylated proteins may act as growth factors via the Man-6-P/IGF-II receptor. In conclusion, the gene expression and mechanism of action of IGF-II is very complex suggesting that its biological actions can be regulated at different levels including the transcription, translation, posttranslational processing, receptor binding and intracellular signalling.
Gammeltoft
S
S
Department of Clinical Chemistry, Bispebjerg Hospital, Copenhagen, Denmark.
Christiansen
J
J
Nielsen
F C
FC
Verland
S
S
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008360:Mannosephosphates; D014176:Protein Biosynthesis / Q000235:genetics; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface / Q000502:physiology
D002352:Carrier Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D008360:Mannosephosphates; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D007335:Insulin-Like Growth Factor II; D011505:Protein-Tyrosine Kinases