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 (PIP(3)) by class I phosphoinositide 3 kinases (PI3K). Defective PIP(3) signaling impairs almost every aspect of hematopoiesis, including T cell development and function. Limiting PIP(3) signaling is particularly important, because excessive PIP(3) function in lymphocytes can transform them and cause blood cancers. Here, we review the key functions of PIP(3) and related phosphoinositides in hematopoietic cells, with a special focus on those mechanisms dampening PIP(3) production, turnover, or function. Recent studies have shown that beyond “canonical” turnover by the PIP(3) phosphatases and tumor suppressors phosphatase and tensin homolog (PTEN) and SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1/2), PIP(3) function in hematopoietic cells can also be dampened through antagonism with the soluble PIP(3) analogs inositol(1,3,4,5)tetrakisphosphate (IP(4)) and inositol-heptakisphosphate (IP(7)). Other evidence suggests that IP(4) can promote PIP(3) function in thymocytes. Moreover, IP(4) or the kinases producing it limit store-operated Ca(2+) 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 IP(4) activity in immune cells and highlight contributions of impaired inositol phosphate functions in disorders such as Kawasaki disease, common variable immunodeficiency, or blood cancer.