Editors' ChoiceCell Biology

p85α homodimerizes

Sci. Signal.  11 Aug 2015:
Vol. 8, Issue 389, pp. ec224
DOI: 10.1126/scisignal.aad1973

Phosphoinositide 3-kinase (PI3K) and the phosphatase PTEN control a lipid signaling pathway that regulates many metabolic and growth processes and are commonly mutated in cancer. Class I PI3Ks are heterodimeric kinases composed of a regulatory subunit, such as p85α, and a catalytic subunit, such as p110α. PI3Ks produce phosphatidylinositol 3,4,5-triphosphate (PIP3) from phosphatidylinositol 4,5-bisphosphate (PIP2), and PTEN dephosphorylates PIP3. p85α can form homodimers, but the biological importance of this was unclear. Cheung et al. identified the domains of p85α that mediated formation and stabilization of p85α homodimers and mediated binding of p85α homodimers with PTEN in cultured human endometrial cancer KLE cells. The regions involved in homodimerization and PTEN interaction were distinct from those that mediate binding of p85α to p110α. Analysis of immunoprecipitates from cells expressing various wild-type and mutant forms of p85α showed that monomeric p85α bound to p110α, whereas homodimeric p85α bound to PTEN. p85α homodimers enhanced the stability of PTEN, by reducing ubiquitylation of PTEN, and increased the abundance of PTEN at the plasma membrane in KLE cells. Coimmunoprecipitation experiments showed that the presence of p85α homodimers reduced binding of PTEN to the E3 ubiquitin ligase WWP2 and indicated that p85α and WWP2 competed for binding to PTEN. Furthermore, binding of p85α homodimers to PTEN enhanced the association of PTEN with the plasma membrane and promoted the lipid phosphatase activity of PTEN. The authors identified mutations in human cancer samples that mapped to regions of p85α involved in homodimerization. When engineered into p85α and overexpressed in cultured mouse and human cells, these mutations interfered with p85α homodimerization, increased ubiquitylation of PTEN, and promoted prosurvival signaling downstream of PI3K, suggesting that the activities observed for p85α homodimers in cell culture may be relevant in vivo.

L. W. Cheung, K. W. Walkiewicz, T. M. Besong, H. Guo, D. H. Hawke, S. T. Arold, G. B. Mills, Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium. eLife 4, e06866 (2015). [PubMed]