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Type: Journal article
Title: p84 forms a negative regulatory complex with p110γ to control PI3Kγ signalling during cell migration
Other Titles: p84 forms a negative regulatory complex with p110gamma to control PI3Kgamma signalling during cell migration
Author: Turvey, M.
Klingler-Hoffmann, M.
Hoffmann, P.
McColl, S.
Citation: Immunology and Cell Biology, 2015; 93(8):735-743
Publisher: Nature Publishing Group
Issue Date: 2015
ISSN: 0818-9641
Statement of
Michelle E Turvey, Manuela Klingler-Hoffmann, Peter Hoffmann and Shaun R McColl
Abstract: Phosphoinositide 3-kinase γ (PI3Kγ) consists of the catalytic subunit p110γ that forms a mutually exclusive heterodimer with one of two adaptor subunits, p101 or p84. Whilst activation of PI3Kγ is necessary for cell migration downstream of GPCR engagement, particularly within the immune system, aberrant PI3Kγ signaling 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 signaling. The present study investigated the role of p84 phosphorylation in the context of PI3Kγ signaling, cell migration and p84-mediated tumour suppression. Two putative phosphorylation sites were characterised within p84, Ser358 and Thr607. Expression of wildtype 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 induction of p84/p110γ dimers. The dimerisation of wildtype 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.Immunology and Cell Biology accepted article preview online, 10 March 2015. doi:10.1038/icb.2015.35.
Keywords: Cell Line
Multiprotein Complexes
Receptors, G-Protein-Coupled
Recombinant Fusion Proteins
Signal Transduction
Cell Movement
Gene Expression
Protein Processing, Post-Translational
Amino Acid Sequence
Protein Binding
Molecular Sequence Data
Proto-Oncogene Proteins c-akt
Chemokine CXCL12
Protein Multimerization
Class Ib Phosphatidylinositol 3-Kinase
Rights: © 2015 Australasian Society for Immunology Inc. All rights reserved
DOI: 10.1038/icb.2015.35
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