Regulation of Hematopoietic Cell Development and Function Through Phosphoinositides.
One of the most paramount receptor-induced signal transduction mechanisms in hematopoietic cells is production of the lipid second messenger phosphatidylinositol(3,4,5)trisphosphate (PIP3) by class I phosphoinositide 3 kinases (PI3K). Defective PIP3 signaling impairs almost every aspect of hematopoiesis, including T cell development and function. Limiting PIP3 signaling is particularly important, because excessive PIP3 function in lymphocytes can transform them and cause blood cancers. Here, we review the key functions of PIP3 and related phosphoinositides in hematopoietic cells, with a special focus on those mechanisms dampening PIP3 production, turnover, or function. Recent studies have shown that beyond "canonical" turnover by the PIP3 phosphatases and tumor suppressors phosphatase and tensin homolog (PTEN) and SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1/2), PIP3 function in hematopoietic cells can also be dampened through antagonism with the soluble PIP3 analogs inositol(1,3,4,5)tetrakisphosphate (IP4) and inositol-heptakisphosphate (IP7). Other evidence suggests that IP4 can promote PIP3 function in thymocytes. Moreover, IP4 or the kinases producing it limit store-operated Ca2+ entry through Orai channels in B cells, T cells, and neutrophils to control cell survival and function. We discuss current models for how soluble inositol phosphates can have such diverse functions and can govern as distinct processes as hematopoietic stem cell homeostasis, neutrophil macrophage and NK cell function, and development and function of B cells and T cells. Finally, we will review the pathological consequences of dysregulated IP4 activity in immune cells and highlight contributions of impaired inositol phosphate functions in disorders such as Kawasaki disease, common variable immunodeficiency, or blood cancer.
['Elich|Mila|M|', 'Sauer|Karsten|K|']
D000818:Animals D015415:Biomarkers D002118:Calcium D002454:Cell Differentiation D002470:Cell Survival D060966:Clonal Selection, Antigen-Mediated D006410:Hematopoiesis D006412:Hematopoietic Stem Cells D006801:Humans D007249:Inflammation D007295:Inositol Phosphates D009504:Neutrophils D019869:Phosphatidylinositol 3-Kinases D010716:Phosphatidylinositols D000081082:Phosphoinositide-3 Kinase Inhibitors D017853:Phosphotransferases (Alcohol Group Acceptor) D011485:Protein Binding D015398:Signal Transduction D060168:Thymocytes
phosphoinositide 3 kinase phosphatase and tensin homolog ORAI Kawasaki disease AKT ITPKB/IP3-3KB/IP3KB ITPKC/IP3-3KC/IP3KC SH2 domain-containing inositol-5-phosphatase