PI3Kβ goes to the head of its class

Phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases that phosphorylate the 3-hydroxyl group of phosphatidyl inositol (PtdIns), as well as the phosphoinositides PtdIns-4-phosphate [PI(4)P] and PtdIins-4,5-bisphosphate [PI(4,5)P₂], to generate PI(3)P, PI(3,4)P₂, and PI(3,4,5)P₃, respectively, on the inner leaflet of the plasma membrane.²  Members of the PI3K family are grouped into 3 classes (classes I, II, and III) based on their structural properties and substrate specificities. Class I PI3Ks are heterodimers composed of a 110-kDa catalytic subunit (p110) and a regulatory subunit, whereas class II and class III PI3Ks each consist of a single catalytic subunit.²  The ability to generate PI(3,4,5)P₃ is unique to class I PI3Ks, which are the only PI3K family members that can use PI(4,5)P₂ as a substrate.²  All of the lipid products of PI3Ks support recruitment of pleckstrin homology (PH) domain–containing proteins that propagate transduction of an activating signal; however, the lipid product PI(3,4,5)P₃ has garnered particular attention because it serves as a high-affinity docking site for the PH domains of the serine/threonine kinases Akt (also known as protein kinase B or PKB) and 3-phosphoinositide–dependent protein kinase 1 (PDK1).³  Once recruited to locations in the membrane where class I PI3Ks are active, PDK1 phosphorylates and activates Akt, which goes on to phosphorylate multiple target molecules that control cell metabolism, survival, proliferation, and motility.⁴ 

The class I PI3K subfamily is divided into 2 subclasses (IA and IB) on the basis of the regulatory subunit with which the p110 catalytic subunit associates. This in turn determines the nature of the receptors with which p110 will be brought into proximity as well as the mechanism by which p110 is activated (see panel A of the figure). The catalytic subunits of class IA PI3Ks, of which there are 3 (p110α, p110β, and p110δ), associate with 1 of 5 regulatory subunits, collectively referred to as p85, to create a PI3Kα, PI3Kβ, or PI3Kδ heterodimer, respectively.^2-4  Binding of p110α, p110β, or p110δ to p85 maintains the class IA PI3K in an inactive conformation in resting cells; however, p85 contains 2 Src homology 2 (SH2) domains that are capable of binding to phosphotyrosine residues on receptors or adaptor molecules.^3,4  Binding of p85 to phosphotyrosine-containing molecules at the plasma membrane serves to recruit and activate class IA PI3Ks at locations along the plasma membrane where tyrosine kinases have been activated. Consequently, class IA PI3Ks are activated primarily by receptor tyrosine kinases (RTKs) or immunoreceptor tyrosin-based activation motif (ITAM)–coupled receptors that use tyrosine kinases to initiate signal transduction. Instead of associating with p85, the catalytic subunit of the sole member of the class IB subfamily of PI3Ks (p110γ) associates with 1 of 2 alternative regulatory subunits, including p101 and the p101 homologue, p84 (also known as PI3Kγ adaptor protein of 87 kDa or p87PIKAP), to create the PI3Kγ heterodimer.³  The p101 and p84/87 regulatory subunits are thought to facilitate activation of p110γ by G protein βγ subunits.²  Consequently, PI3Kγ is not activated by events that trigger tyrosine kinase activity but is instead activated by G protein–coupled receptors (GPCRs). Interestingly, PI3Kβ, but not other class IA PI3Ks, shares with PI3Kγ the ability to be activated by GPCRs; however, the mechanism underlying GPCR-mediated activation of p110β is not well understood.^2,3 

The work of Canobbio et al in this issue of Blood contributes to an extensive and growing body of literature that has defined an important role for PI3K activity in platelet activation by GPCRs and ITAM-bearing receptors.⁵  They make use of 2 types of new tools, specifically, a PI3Kβ-specific small molecule inhibitor and genetically engineered mice that express “kinase dead” forms of PI3Kβ and PI3Kγ, to define the relative importance and specific functions of PI3Kβ and PI3Kγ in platelet activation by different agonists. They demonstrate that PI3Kβ and PI3Kγ activities each contribute minimally and redundantly to platelet activation by the GPCRs for ADP and thromboxane, in a manner that is at least partially uncoupled from their involvement in Akt activation (panel B, right, in the figure). More importantly, they show that PI3Kβ activity is uniquely required for platelet activation by GPVI and α_IIbβ₃, both of which use ITAM-containing signaling subunits to activate platelets (panel B, left, in the figure). These findings are comfortingly compatible with our understanding of the mechanisms by which PI3Kβ and PI3Kγ are activated (ie, PI3Kβ can be activated by both GPCRs and tyrosine kinase-activating receptors, whereas PI3Kγ is activated only by GPCRs). Furthermore, the results are useful in that they focus our attention on PI3Kβ as the sole PI3K isoform involved in GPVI- and α_IIbβ₃-mediated platelet activation.