p110δ PI3 kinase pathway: emerging roles in cancer

Abstract

Class IA PI3Ks consists of three isoforms of the p110 catalytic subunit designated p110α, p110β, and p110δ which are encoded by three separate genes. Gain-of-function mutations on PIK3CA gene encoding for p110α isoform have been detected in a wide variety of human cancers whereas no somatic mutations of genes encoding for p110β or p110δ have been reported. Unlike p110α and p110β which are ubiquitously expressed, p110δ is highly enriched in leukocytes and thus the p110δ PI3K pathway has attracted more attention for its involvement in immune disorders. However, findings have been accumulated showing that the p110δ PI3K plays a seminal role in the development and progression of some hematologic malignancies. A wealth of knowledge has come from studies showing the central role of p110δ PI3K in B-cell functions and B-cell malignancies. Further data have documented that wild-type p110δ becomes oncogenic when overexpressed in cell culture models and that p110δ is the predominant isoform expressed in some human solid tumor cells playing a prominent role in these cells. Genetic inactivation of p110δ in mice models and highly-selective inhibitors of p110δ have demonstrated an important role of this isoform in differentiation, growth, survival, motility, and morphology with the inositol phosphatase PTEN to play a critical role in p110δ signaling. In this review, we summarize our understanding of the p110δ PI3K signaling pathway in hematopoietic cells and malignancies, we highlight the evidence showing the oncogenic potential of p110δ in cells of non-hematopoietic origin and we discuss perspectives for potential novel roles of p110δ PI3K in cancer.

Keywords: PTEN; cancer; hematologic malignancies; p110δ PI3K; solid tumors.

Figure 1

Simplified scheme showing the differential activation of class IA and class IB PI3K isoforms. Class IA PI3Ks are heterodimers consisting of a 110 kDa catalytic subunit (p110α, p110β, and p110δ) in complex with a p85 regulatory subunit, of which five isoforms exist. Class IA PI3Ks are activated by growth factor and cytokine receptors or adaptor proteins (e.g., CD19/BCAP in B cells). Binding of the ligand to its receptor leads to receptor dimerization and auto-phosphorylation of tyrosines (Y) which are located in pYxxM motifs. The p85 regulatory subunits have Src-homology 2 (SH2) domains which bind to phosphorylated tyrosines in YxxM motifs recruiting thus the class IA PI3Ks to the plasma membrane where their lipid substrates are located. Class IB PI3K consists of the p110γ isoform which binds to p101 or p84 regulatory subunits. Class IB PI3K is activated by G protein-coupled receptors (GPCRs). Binding of the ligand (e.g., a chemokine) to its cognate GPCR induces the dissociation of heterotrimeric G-proteins and the Gβγ subunits interact with the class IB PI3K. Arrows with dashed lines represent activation of p110β and p110δ downstream of GPCRs and activation of p110γ downstream of tyrosine kinases by currently unknown mechanisms.

Figure 2

Simplified scheme showing the critical role of Class IA PI3Ks in multiple cellular functions. Upon PI3Ks activation, PI(3,4,5)P3 is produced and recruits Akt at the cell membrane where it becomes phosphorylated at The308 by PDK1 and at Ser473 by mTORC2. Fully activated Akt phosphorylates a variety of effector molecules including the TSC1/2, BAD, FOXO, GSK-3β, and p27 which then control cell growth, metabolism, survival, cell cycle, or migration. PI(3,4,5)P3 also activates GEFs or GAPs which then regulate the activity of small GTPases controlling cell motility. The PI(3,4,5)P3 levels produced by PI3Ks are regulated by the PTEN phosphatase which counteracts the PI3K reaction by dephosphorylating the 3-position of the inositol ring of PI(3,4,5)P₃ yielding back PI(4,5)P₂.

Figure 3

p110δ PI3K pathway in B cells. Engagement of BCRs by antigen induces the phosphorylation of ITAMs in the cytoplasmic tails of Ig-α and Ig-β by Lyn leading to recruitment and activation of Syk via ITAMs and to initiation of downstream signaling cascade. Tyrosine phosphorylation of the co-receptor CD19 and BCAP recruits p110δ PI3K through SH2 interactions leading to production of PI(3,4,5)P3 which recruits PH-domain containing proteins such as Akt, Btk, and PLCγ2. Akt controls the activity of multiple signaling molecules and pathways such as the mTORC1, GSK-3, and the NF-kB pathway. Btk phosphorylates and activates PLCγ2 which then catalyzes the hydrolysis of PI(4,5)P2 yielding I(3,4,5)P3 and diacylglycerol (DAG). I(3,4,5)P3 initiates Ca2+ mobilization and DAG induces the activation of protein kinase C (PKC) isoforms. The p110δ PI3K also functions downstream of the cytokine receptors BAFFR and IL6R, which are activated by BAFF and IL-6, respectively, derived from lymphoid stromal cells, and downstream of the IL4R which is activated by IL-4 derived from T cells. Chemokine receptors (CXCR5) and co-stimulatory receptors (CD40, TLRs) also induce the activation of p110δ PI3K in B cells.

Figure 4

p110δ PI3K mediates the effects of CSF-1 or EGF via RhoA and PTEN in macrophages and some solid tumor cells. Activation of p110δ leads to increased activity of p190RhoGAP (through PYK2/Src activation) and to cytoplasmic accumulation of p27 (which is mediated by the increased Akt activity). p190RhoGAP induces the inactivation of RhoA whereas p27 prevents the activation of RhoA both thus leading to reduced RhoA activity and consequently to decreased PTEN activity. Inactivation of p110δ by IC87114 reverses these pathways leading to PTEN activation which then opposes the PI3K reaction of the remaining active p110 isoforms. The p190RhoGAP-driven mechanism almost solely keeps RhoA activity low under basal whereas that of p27 contributes upon stimulated conditions. Arrows with dashed lines represent alterations in activity or location in the presence (red) or in the absence (black) of IC87114.