Gα16 interacts with Class IA phosphatidylinositol 3-kinases and inhibits Akt signaling

Phosphatidylinositol 3-kinase (PI3K) mediates receptor tyrosine kinase and G protein coupled receptor (GPCR) signaling by phosphorylating phosphoinositides to elicit various biological responses. Gαq has previously been shown to inhibit class IA PI3K by interacting with the p110α subunit. However, it is not known if PI3Ks can associate with other Gαq family members such as Gα16. Here, we demonstrated that class IA PI3Ks, p85/p110α and p85/p110β, could form stable complexes with wild type Gα16 and its constitutively active mutant (Gα16QL) in HEK293 cells. In contrast, no interaction between Gα16 and class IB PI3K was observed. The Gα16/p110α signaling complex could be detected in hematopoietic cells that endogenously express Gα16. Overexpression of class I PI3Ks did not inhibit Gα16QL-induced IP3 production and, unlike p63RhoGEF, class IA PI3Ks did not attenuate the binding of PLCβ2 to Gα16QL. On the contrary, the function of class IA PI3Ks was suppressed by Gα16QL as revealed by diminished production of PIP3 as well as inhibition of EGF-induced Akt phosphorylation. Taken together, these results suggest that Gα16 can bind to class IA PI3Ks and inhibit the PI3K signaling pathway.