Phosphoinositide 3-kinase γ (PI3Kγ) consists of the catalytic subunit p110γ that forms a mutually exclusive heterodimer with one of the two adaptor subunits， p101 or p84. Although activation of PI3Kγ is necessary for cell migration downstream of G-protein-coupled receptor engagement， particularly within the immune system， aberrant PI3Kγ signalling has been associated with transformation， increased migration and the progression of multiple cancer types. Regulation of PI3Kγ signal activation and duration is critical to controlling and maintaining coordinated cellular migration; however， the mechanistic basis for this is not well understood. We have recently demonstrated that， in contrast to the ... More
Phosphoinositide 3-kinase γ (PI3Kγ) consists of the catalytic subunit p110γ that forms a mutually exclusive heterodimer with one of the two adaptor subunits， p101 or p84. Although activation of PI3Kγ is necessary for cell migration downstream of G-protein-coupled receptor engagement， particularly within the immune system， aberrant PI3Kγ signalling has been associated with transformation， increased migration and the progression of multiple cancer types. Regulation of PI3Kγ signal activation and duration is critical to controlling and maintaining coordinated cellular migration; however， the mechanistic basis for this is not well understood. We have recently demonstrated that， in contrast to the tumour-promoting potential of p110γ and p101， p84 possesses tumour-suppressor activity， suggesting a negative regulatory role within PI3Kγ signalling. The present study investigated the role of p84 phosphorylation in the context of PI3Kγ signalling， cell migration and p84-mediated tumour suppression. Two putative phosphorylation sites were characterised within p84， Ser358 and Thr607. Expression of wild-type p84 reduced the oncogenic potential of MDA.MB.231 cells and inhibited metastatic lung colonisation in vivo， effects that were dependent on Thr607. Furthermore， loss of Thr607 enhanced migration of MDA.MB.231 cells in vitro and prevented the induction of p84/p110γ dimers. The dimerisation of wild-type p84 with p110γ was not detected at the plasma membrane， indicating an inhibitory interaction preventing PI3Kγ lipid-kinase activity. In contrast， Ser358 phosphorylation was not determined to be critical for p84 activity in the context of migration. Our findings suggest that p84 binding to p110γ may represent a novel negative feedback signal that terminates PI3Kγ activity.
