A specific type of ganglioside as a modulator of insulin-dependent cell growth and insulin receptor tyrosine kinase activity. Possible association of ganglioside-induced inhibition of insulin receptor function and monocytic differentiation induction in HL-60 cells.
Insulin-dependent cell growth has been correlated with insulin receptor function, particularly receptor-associated kinase activity, in in vitro studies. The insulin-dependent phosphorylation of the 95-kDa receptor subunit was clearly inhibited, in a concentration-dependent manner, by the presence of unbranched neolacto series gangliosides having a NeuAc2----3Gal terminus, particularly 2----3-sialosylparagloboside (2----3SPG; IV3NeuAc-nLc4), but not by other gangliosides with a NeuAc2----6Gal terminus or by branched neolacto series gangliosides (e.g. G10). Such inhibition of phosphorylation was minimal with ganglio series gangliosides and negligible with sphingosine, neutral glycolipids, or sulfatide. 2----3SPG did not affect insulin binding to the insulin receptor. Insulin-dependent cell growth and its inhibition by 2----3SPG were observed in three human cell lines so far tested: lymphoid cell line IM9, promyelocytic leukemia cell line HL-60, and erythroleukemia cell line K562. Since IM9 cells contain a much higher quantity of insulin receptor than do HL-60 or K562 cells, insulin-dependent receptor phosphorylation and its inhibition by 2----3SPG in intact cells were clearly observed with IM9 cells. Receptor phosphorylation in intact cells was inhibited when cells were preincubated in the presence of 2----3SPG. Insulin-dependent growth of HL-60 and K562 cells was also inhibited by prolonged culture (96-144 h) with exogenous 2----3SPG. Subsequent to the inhibition of insulin-dependent HL-60 cell growth, a remarkable phenotypic transformation was observed, i.e. changes in morphology, enzymes, and cell-surface markers to those characteristic of monocytes. The level of 2----3SPG in HL-60 cells increased when cells were cultured with 1 alpha,25-dihydroxyvitamin D3 to the same degree seen in cells cultured with 5 microM 2----3SPG. Both these treatments led to inhibition of insulin-dependent cell growth, followed by induction of monocytic differentiation. Thus, the cellular level of 2----3SPG may modulate insulin-dependent cell growth and define the lineage specificity of differentiation through modulation of receptor-associated kinase activity.
Nojiri
H
H
Biomembrane Institute, Seattle, Washington 98119.
Stroud
M
M
Hakomori
S
S
D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002240:Carbohydrate Sequence; D002454:Cell Differentiation; D002455:Cell Division; D005732:Gangliosides / Q000502:physiology*; D005915:Globosides / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007951:Leukemia, Myeloid; D008214:Lymphocytes / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D013110:Sphingosine / Q000494:pharmacology; D013433:Sulfoglycosphingolipids / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D015214:Antigens, Differentiation, Myelomonocytic; D005732:Gangliosides; D005915:Globosides; D007328:Insulin; D013433:Sulfoglycosphingolipids; C036363:paragloboside; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D013110:Sphingosine