Regulation of Hematopoietic Cell Development and Function Through Phosphoinositides

Abstract

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.

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

“…SHIP-1 is a negative regulator of cell signaling in a variety of hematopoietic cells through phosphoinositide; and it dephosphorylates PIP3 to PI-3,4-bisphosphate, effectively reducing or terminating the downstream signaling of the PI3K pathway. 33 SHIP-1 participates in the process of several lung diseases such as asthma, lung injury, and chronic obstructive pulmonary disease. 5,34,35 Evidence showed that SHIP-1 KO mice develop a series of pathologies characterized by progressive non-resolving lung inflammation, fibrosis, and emphysema.…”

Regulation of Hematopoietic Stem Cell Fate and Malignancy

“…Upon resolution of the stress, PI3K inactivation is required for the re-entry of HSCs into quiescence. Thus, PI3K activity in HSCs needs to be tuned into an appropriate window [ 5 , 79 ].…”

“…Thus, PI3K is considered to be a promising target for therapy and PI3K inhibitors are mainly used for chemotherapeutic agents for hematological malignancies [ 76 ]. The PI3Kδ inhibitor, Idelalisib, has been approved for treating relapsed chronic lymphocytic leukemia (CLL), follicular B-cell non-Hodgkin lymphoma, and small lymphocytic Lymphoma [ 78 , 79 ]. Other PI3K inhibitors including S14161, the p110α-selective inhibitor AS702630, the p110β-selective inhibitor TGX-115, and the p110δ inhibitors IC87114 and CAL-10180 have been developed and regulate the proliferation and survival of leukemic blasts [ 76 ].…”

Plasmodium infection prevents recurrence and metastasis of hepatocellular carcinoma potentially via inhibiting EMT

“…PI3K activates and produces second messenger PIP3, which activates AKT through phosphorylation of AKT protein at Ser308 [23]. GSK-3β is a downstream target of phosphorylated AKT, which promotes the degradation of Snail, while phosphorylation of GSK-3β leads to its inactivation.…”