Journal of Biological Chemistry
Volume 295, Issue 47, 20 November 2020, Pages 16100-16112
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A structural view of PA2G4 isoforms with opposing functions in cancer

https://doi.org/10.1074/jbc.REV120.014293Get rights and content
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The role of proliferation-associated protein 2G4 (PA2G4), alternatively known as ErbB3-binding protein 1 (EBP1), in cancer has become apparent over the past 20 years. PA2G4 expression levels are correlated with prognosis in a range of human cancers, including neuroblastoma, cervical, brain, breast, prostate, pancreatic, hepatocellular, and other tumors. There are two PA2G4 isoforms, PA2G4-p42 and PA2G4-p48, and although both isoforms of PA2G4 regulate cellular growth and differentiation, these isoforms often have opposing roles depending on the context. Therefore, PA2G4 can function either as a contextual tumor suppressor or as an oncogene, depending on the tissue being studied. However, it is unclear how distinct structural features of the two PA2G4 isoforms translate into different functional outcomes. In this review, we examine published structures to identify important structural and functional components of PA2G4 and consider how they may explain its crucial role in the malignant phenotype. We will highlight the lysine-rich regions, protein-protein interaction sites, and post-translational modifications of the two PA2G4 isoforms and relate these to the functional cellular role of PA2G4. These data will enable a better understanding of the function and structure relationship of the two PA2G4 isoforms and highlight the care that will need to be undertaken for those who wish to conduct isoform-specific structure-based drug design campaigns.

proliferation-associated protein 2G4 (PA2G4)
ErbB3-binding protein 1 (EBP1)
cancer
drug target
structure-function
receptor structure-function
protein targeting
cancer biology

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Funding and additional information—This work was supported by National Health and Medical Research Council (NHMRC) Australia Project Grant GNT1125171, an SVI Top-up scholarship (to B. W. S.), an NHMRC Senior Principal Research Fellowship (to M. W. P.), a 5-Point Foundation Postdoctoral Fellowship (to J. K. H.), NHMRC Program Grant GNT1016699 (to G. M. M.), Cancer Institute NSW Program Grant 10/TPG/1-13 (to G. M. M.), Cancer Council NSW Program Grant PG-11-06 (to G. M. M.), and Neuroblastoma Australia (to G. M. M. and B. B. C.).

Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.

Abbreviations—The abbreviations used are:

    aa

    amino acids

    PDB

    Protein Data Bank

    RMSD

    root mean square deviation

    MAP

    methionine aminopeptidase

    eIF2α

    eukaryotic initiation factor 2α

    IRES

    internal ribosome entry site

    ITAF

    IRES-trans-acting factor

    AR

    androgen receptor

    PI3K

    phosphatidylinositol 3-kinase

    Rb

    retinoblastoma

    PSA

    prostate-specific antigen

    MAPK

    mitogen-activated protein kinase.