PI3Kβ downstream of GPCRs – crucial partners in oncogenesis

Of the class IA PI3Ks, p110β is the only member to simultaneously signal downstream of both Receptor Tyrosine Kinases (RTKs) and G Protein-Coupled Receptors (GPCRs). While the mechanism of RTK-mediated activation of p85/p110 heterodimers has been characterized [1, 2], defining the mechanism of Gβγ-mediated activation of p110β downstream of GPCRs has been challenging due to the transient nature of the interaction. The binding of p110β to Gβγ is weak, but is reinforced by interactions with lipid membranes, where Gβγ resides. A combination of sequence analysis and hydrogen/deuterium exchange (HDX) coupled to mass spectrometry (MS) experiments has enabled us to map the regions of interaction on both p110β and Gβγ [3]. Furthermore, HDX-MS data analysis provided a uniqu