Impact of p85α Alterations in Cancer.

Jeremy D S Marshall,Paul Mellor,Dielle E Whitecross,Deborah H Anderson

doi:10.3390/biom9010029

Jeremy D S Marshall, Paul Mellor + Show 2 more

Open Access

https://doi.org/10.3390/biom9010029

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Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in the regulation of cell signaling, proliferation, survival, migration and vesicle trafficking in normal cells and is frequently deregulated in many cancers. The p85α protein is the most characterized regulatory subunit of the class IA PI3Ks, best known for its regulation of the p110-PI3K catalytic subunit. In this review, we will discuss the impact of p85α mutations or alterations in expression levels on the proteins p85α is known to bind and regulate. We will focus on alterations within the N-terminal half of p85α that primarily regulate Rab5 and some members of the Rho-family of GTPases, as well as those that regulate PTEN (phosphatase and tensin homologue deleted on chromosome 10), the enzyme that directly counteracts PI3K signaling. We highlight recent data, mapping the interaction surfaces of the PTEN–p85α breakpoint cluster region homology (BH) domain, which sheds new light on key residues in both proteins. As a multifunctional protein that binds and regulates many different proteins, p85α mutations at different sites have different impacts in cancer and would necessarily require distinct treatment strategies to be effective.

Highlights

Class IA phosphatidylinositol 3-kinase (PI3Ks) consist of an 85 kDa regulatory subunit (p85), partnered with a 110 kDa catalytic subunit (p110)
In addition to the C-terminal domains, the larger p85 isoforms contain N-terminal regions that include: an SH3 (Src homology 3) domain and a breakpoint cluster region homology (BH) domain that has GTPase activating protein (GAP) activity (Figure 1). These regions bind to small GTPases and the lipid phosphatase PTEN
PTEN is composed of five domains: a plasma membrane binding domain that binds PI4,5P2 (PMB), a dual lipid/protein phosphatase domain (PASE), a C2 domain (C2), a Ser/Thr rich regulatory domain (REG), and a PDZ binding domain (PDZB)

Summary

Introduction

Class IA phosphatidylinositol 3-kinase (PI3Ks) consist of an 85 kDa regulatory subunit (p85), partnered with a 110 kDa catalytic subunit (p110). Most PIK3CA mutations are gain-of-function mutations that activate p110α, resulting in increased downstream Akt signaling, promoting aberrant cell survival and tumorigenesis The majority of these mutations occur in hotspots in either the kinase or helical domains and are oncogenic mutations (Figure 3a) [38,39,40,41]. The cancer-associated H1047R mutation is located within the p110α kinase domain (Figure 3a) and results in catalytic activation that still requires p85α binding, but is independent of. The cancer-associated E542K and E545K mutations are located within the helical domain (Figure 3a) and these p110α mutants still require binding to Ras [27] These mutations activate p110α by disrupting the inhibitory interactions with the p85α nSH2 domain (residues K379 and R340) [42,43]. Figures were generated using cBioPortal [30,31]

Small GTPases–p85α Interactions and Alterations

PTEN–p85α Interactions and Alterations

Characterizing Variants of Unknown Significance

Findings

Conclusions