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Novel functions of phosphatidylinositol 3-kinase in terminally differentiated cells
S Nakanishi1, H Yano, Y Matsuda
1Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd. Japan.
Abstract:
Importance of phosphatidylinositol 3-kinase (PI 3-kinase) in signalling pathways leading to growth stimulation has already been reviewed in this journal and others. Evidence has now been accumulating that PI 3-kinase is involved in transmission of activation signals in terminally differentiated cells, especially signals starting from receptors which have no intrinsic tyrosine kinase domain. The pioneer works showed the presence of PI 3-kinase activity and the accumulation of the reaction products of PI 3-kinase correlated with the cell responses. However, these studies were done in only limited cell responses such as respiratory burst in neutrophils and degranulation in platelets. Recent finding of a potent and selective inhibitor of PI 3-kinase, wortmannin, reported from three independent groups including us, gave a new and powerful tool not only to confirm the suggested functions but also to reveal new functions of PI 3-kinase such as histamine release from antigen-stimulated mast cells/basophils and glucose uptake in insulin-stimulated adipocytes. Nearly one hundred papers which describe the action of wortmannin on various cells have been reported during one year after the publication of the discovery of wortmannin as PI 3-kinase inhibitor, suggesting possible involvement of the enzyme in the diverse cell responses besides cell proliferation.
Insights
Phosphatidylinositol 3-kinase (PI 3-kinase) plays a crucial role in cell signaling beyond growth. New research highlights its involvement in diverse cellular responses, including histamine release and glucose uptake, particularly in differentiated cells.
Area of Science:
- Cell Biology
- Biochemistry
- Signal Transduction
Background:
- Phosphatidylinositol 3-kinase (PI 3-kinase) is known for its role in growth stimulation pathways.
- Emerging evidence suggests PI 3-kinase involvement in signal transmission within terminally differentiated cells, especially those with receptors lacking intrinsic tyrosine kinase domains.
- Initial studies linked PI 3-kinase activity to specific cellular responses like neutrophil respiratory burst and platelet degranulation.
Purpose of the Study:
- To explore the broader functions of PI 3-kinase in cellular signaling.
- To investigate the role of PI 3-kinase in differentiated cells using a novel inhibitor.
- To identify new cellular processes regulated by PI 3-kinase.
Main Methods:
- Utilized wortmannin, a potent and selective PI 3-kinase inhibitor.
- Correlated PI 3-kinase activity with specific cell responses.
- Investigated PI 3-kinase involvement in histamine release and glucose uptake.
Main Results:
- Wortmannin confirmed previously suggested functions of PI 3-kinase.
- Identified novel roles for PI 3-kinase in histamine release from mast cells/basophils and glucose uptake in adipocytes.
- Over 100 papers published within a year of wortmannin's discovery indicate its widespread involvement in various cell responses.
Conclusions:
- PI 3-kinase is implicated in a diverse array of cellular functions beyond cell proliferation.
- The discovery of wortmannin has significantly advanced the understanding of PI 3-kinase's multifaceted roles in cell signaling.
- PI 3-kinase is a key mediator in signal transmission across various cell types and responses.