Phosphatidylinositol-3,4,5-trisphosphate: tool of choice for class I PI 3-kinases

Abstract

Class I PI 3-kinases signal by producing the signaling lipid phosphatidylinositol(3,4,5) trisphosphate, which in turn acts by recruiting downstream effectors that contain specific lipid-binding domains. The class I PI 3-kinases comprise four distinct catalytic subunits linked to one of seven different regulatory subunits. All the class I PI 3-kinases produce the same signaling lipid, PIP3, and the different isoforms have overlapping expression patterns and are coupled to overlapping sets of upstream activators. Nonetheless, studies in cultured cells and in animals have demonstrated that the different isoforms are coupled to distinct ranges of downstream responses. This review focuses on the mechanisms by which the production of a common product, PIP3, can produce isoform-specific signaling by PI 3-kinases.

Figure 1. Domain Organization and Activators of Class I PI 3-kinases

The Class IA PI 3-kinases consist of a p85 regulatory subunit containing SH3, BCR, proline-rich, SH2 and coiled-coil (iSH2) domains, and a p110 catalytic subunit (in yellow) containing an Adapter Binding Domain (ABD), a Ras Binding Domain (RBD), C2, helical and kinase domains. Shorter isoforms of p85 (p55α, p50α, p55γ) contain a truncated N-terminal segment linked to the first SH2 domain. The Class IB PI 3-kinase consists of structurally uncharacterized p87/84 or p101 regulatory subunits bound to a p110γ catalytic subunit (in yellow), whose domain organization is similar to that of Class IA PI 3-kinases. The mechanism of p87/p101 binding to p110γ is not yet known, but involves both the N- and C-terminal regions of p110γ [120]. Of the upstream activators shown, Ras binding regulates p85/p110α and p85/p110δ but not p85/p110β. Gγ regulates p85/p110β and p101/p110γ but not p85/p110α or p85/p110δ.

Figure 2. Pathways to isoform-specific PI 3-kinase activation

While no one PI 3-kinase activator yields specific or preferential activation of any one PI 3-kinase isoform, combinations of activators and distinct activator locations could allow differential activation of distinct PI 3-kinases.