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Published on: July 21, 2018
Human tumor mutants in the p110alpha subunit of PI3K
Zhenning Liu1, Thomas M Roberts
1Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
The PI3K-Akt pathway is frequently upregulated in human tumors. Recently, somatic mutations of PIK3CA, encoding p110alpha catalytic subunit of Class IA PI3Ks, have been found in various cancers. The two most common types of p110alpha mutants, those in the helical and kinase domains, have been shown to be very potent in Akt activation and oncogenic transformation by several groups. Notably these common mutations may not enhance recruitment of p110alpha to the plasma membrane where its substrates are located. We have investigated the effect of membrane localization on common PIK3CA tumor mutants via myristoylation. In addition we have studied a third class of less frequent mutants in the p85-binding domain, in an attempt to gain insight into p85's inhibitory effect on p110alpha. This article briefly reviews and extends the literature on mutant forms of p110alpha.
Insights
Common PIK3CA mutations in cancer may not require plasma membrane localization for oncogenic activity. This study investigates membrane targeting and p85 inhibition in p110alpha mutants.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The PI3K-Akt pathway is crucial in human cancers and frequently upregulated.
- Somatic mutations in PIK3CA, encoding the p110alpha subunit of PI3K, are prevalent in various cancers.
Purpose of the Study:
- Investigate the impact of membrane localization on common PIK3CA tumor mutants using myristoylation.
- Examine less frequent p85-binding domain mutants to understand p85's inhibitory role on p110alpha.
Main Methods:
- Myristoylation to study membrane localization effects.
- Analysis of p85-binding domain mutants.
Main Results:
- Common p110alpha mutants may activate Akt and drive oncogenic transformation independently of enhanced plasma membrane recruitment.
- Investigated the influence of membrane targeting on mutant p110alpha activity.
Conclusions:
- Mutant p110alpha forms contribute to cancer development through various mechanisms.
- Understanding these mutants offers insights into targeted cancer therapies.
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