p84 forms a negative regulatory complex with p110γ to control PI3Kγ signalling during cell migration.

Area of Science:

• Cellular Biology
• Molecular Biology
• Cancer Research

Background:

• Phosphoinositide 3-kinase γ (PI3Kγ) signaling is crucial for cell migration, especially in the immune system.
• Aberrant PI3Kγ signaling contributes to cancer progression, highlighting the need to understand its regulation.
• The adaptor protein p84 exhibits tumor-suppressive activity, contrasting with the oncogenic roles of other PI3Kγ subunits.

Purpose of the Study:

• To investigate the role of p84 phosphorylation in PI3Kγ signaling, cell migration, and tumor suppression.
• To characterize the functional significance of specific phosphorylation sites within p84, namely Ser358 and Thr607.

Main Methods:

• Expression of wild-type and mutant p84 in MDA.MB.231 cancer cells.
• Assessment of oncogenic potential and metastatic colonization in vivo.
• In vitro analysis of cell migration and p84/p110γ dimer formation.

Main Results:

• Wild-type p84 expression reduced cancer cell oncogenicity and lung metastasis, dependent on Thr607 phosphorylation.
• Loss of Thr607 phosphorylation enhanced cell migration and disrupted p84/p110γ dimerization.
• p84/p110γ dimerization was not observed at the plasma membrane, suggesting an inhibitory interaction.

Conclusions:

• p84's tumor-suppressive function is mediated through Thr607 phosphorylation.
• p84 binding to p110γ acts as a negative feedback mechanism to inhibit PI3Kγ lipid kinase activity.
• Understanding p84 phosphorylation offers a potential therapeutic strategy for cancers driven by PI3Kγ signaling.