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Open Access Highly Accessed Research article

Autophosphorylation of serine 608 in the p85 regulatory subunit of wild type or cancer-associated mutants of phosphoinositide 3-kinase does not affect its lipid kinase activity

Meredith J Layton1, Mirette Saad2, Nicole L Church7, Richard B Pearson1346, Christina A Mitchell1 and Wayne A Phillips1245*

Author Affiliations

1 The Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 3800, Australia

2 Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, VIC, 3002, Australia

3 Cancer Signalling Laboratory, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, VIC, 3002, Australia

4 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia

5 Department of Surgery, St. Vincent's Hospital, University of Melbourne, Parkville, VIC, 3010, Australia

6 Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, 3010, Australia

7 The Ludwig Institute for Cancer Research, Royal Melbourne Hospital, PO Box 2008, Parkville, 3050, Australia

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BMC Biochemistry 2012, 13:30  doi:10.1186/1471-2091-13-30

Published: 27 December 2012

Abstract

Background

The α-isoform of the Type 1A Phosphoinositide 3-kinases (PI3Kα) has protein kinase activity as well as phosphoinositide lipid kinase activity. The best described substrate for its protein kinase activity is its regulatory subunit, p85α, which becomes phosphorylated on Serine 608. Phosphorylation of Serine 608 has been reported to down-regulate its lipid kinase activity.

Results

We have assessed whether oncogenic mutants of PI3Kα, which have up-regulated lipid kinase activity, have altered levels of Serine 608 phosphorylation compared to wild type PI3Kα, and whether differential phosphorylation of Serine 608 contributes to increased activity of oncogenic forms of PI3Kα with point mutations in the helical or the kinase domains. Despite markedly increased lipid kinase activity, protein kinase activity was not altered in oncogenic compared to wild type forms of PI3Kα. By manipulating levels of phosphorylation of Serine 608 in vitro, we found no evidence that the protein kinase activity of PI3Kα affects its phosphoinositide lipid kinase activity in either wild-type or oncogenic mutants of PI3Kα.

Conclusions

Phosphorylation of p85α S608 is not a significant regulator of wild-type or oncogenic PI3Kα lipid kinase activity.

Keywords:
PI3K; PIK3CA; Phosphoinositide; Kinase; Mutation; Oncogene; Phosphorylation