Related Experiment Video

Updated: May 8, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

Oncogenic mutations of p110α isoform of PI 3-kinase upregulate its protein kinase activity

Christina M Buchanan1, James M J Dickson, Woo-Jeong Lee

  • 1Department of Molecular Medicine, University of Auckland, Auckland, New Zealand.

Plos One
|August 13, 2013
PubMed

Insights

Class-I PI 3-kinases act as both lipid and protein kinases. Oncogenic mutants of p110α show enhanced protein kinase activity, crucial for cancer therapies targeting PI 3-kinase signaling.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Class-I PI 3-kinases possess both lipid and protein kinase activities.
  • Protein kinase activity targets regulatory sites, including the GM-CSF/IL-3 βc receptor, impacting cell survival in acute myeloid leukemia.
  • Isoform-specific differences in protein kinase activity were previously suggested.

Purpose of the Study:

  • To compare the protein kinase activity of all class-I PI 3-kinase isoforms and two common oncogenic mutants.
  • To investigate autophosphorylation and phosphorylation of the GM-CSF/IL-3 βc receptor fragment (βic) by these kinases.
  • To assess the impact of oncogenic mutations on kinase activity and inhibitor response.

Main Methods:

  • Comparative analysis of autophosphorylation and βic phosphorylation across PI 3-kinase isoforms and mutants.
  • Assessment of kinase activity in the presence of Mg(2+).
  • Evaluation of small molecule inhibitor efficacy against both lipid and protein kinase activities.

Main Results:

  • p110α, p110β, and p110γ effectively phosphorylate βic, while p110δ is less effective.
  • Oncogenic p110α mutants (H1047R, E545K) exhibit enhanced autophosphorylation and βic phosphorylation compared to wild-type.
  • Mutant p110α lipid kinase activity remains sensitive to autophosphorylation inhibition; oncogenic p110α, p110β, and p110γ show Mg(2+)-dependent activity.
  • Differential inhibition patterns observed for various small molecule inhibitors against lipid versus protein kinase activities.

Conclusions:

  • Class-I PI 3-kinase isoforms display distinct protein kinase activities.
  • Oncogenic p110α mutations enhance protein kinase function without compromising lipid kinase regulation by autophosphorylation.
  • The Mg(2+)-dependent protein kinase activity of oncogenic mutants and certain isoforms has significant in vivo implications.
  • Drug development targeting PI 3-kinase must consider isoform-specific and activity-specific inhibitor profiles, especially for cancers with p110α mutations.

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...