A structural view of PA2G4 isoforms with opposing functions in cancer

Abstract

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.

Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures

“…To further explore the functional relevance of the observed templated insertion threads we also searched for potential gene dysregulation effects within the transcriptomic data available for liposarcoma samples in PCAWG 2 . We identified one liposarcoma sample (donor id DO219945), which harbors a templated insertion thread on chromosome 12 whose breakpoints intersect the coding sequence of proliferation-associated protein 2G4 ( PA2G4 ), which can act as a contextual tumor suppressor 54 , in association with reduced PA2G4 expression ( Figure S18A ). Another liposarcoma sample (donor id DO219967) shows strong overexpression of CCND3 , a known sarcoma oncogene, and BYSL , a gene associated with tumor prognosis 55 , in the immediate vicinity of a templated insertion thread ( Figure S18B ).…”

α-Trifluoromethyl Chalcones as Potent Anticancer Agents for Androgen Receptor-Independent Prostate Cancer

“…Glycolytic enzymes, including pyruvate kinase and alpha-enolase, are also related to tumor growth [ 27 ] and reported as diagnostic targets [ 28 ]. The unique target MIC60 plays an important role in the maintenance of mitochondrial crista structure [ 29 ] and PA2G4 isoforms display opposing functions, i.e., suppressive and promoting effects, in cancer [ 30 ]. Compound 5 might suppress cancer cell proliferation mainly by interacting with these proteins.…”

“…The eluted fractions were separated by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Five main bands were detected by staining with Coumassie Brilliant Blue (CBB) dye, corresponding to proteins with molec- role in the maintenance of mitochondrial crista structure [29] and PA2G4 isoforms display opposing functions, i.e., suppressive and promoting effects, in cancer [30]. Compound 5 might suppress cancer cell proliferation mainly by interacting with these proteins.…”

PA2G4 promotes the metastasis of hepatocellular carcinoma by stabilizing FYN mRNA in a YTHDF2-dependent manner

“…PA2G4, also named ErbB3-binding protein 1 (EBP1), was firstly identified by Lamartine et al as an analogue of murine p38-2G4 protein [ 6 ]. PA2G4 has two alternate isoforms, PA2G4-p42 (340 amino acids (aa)) and PA2G4-p48 (394 aa), which both regulate cellular growth and differentiation, but often have opposite effects depending on the context [ 7 , 8 ]. PA2G4-p48 is the predominant form in mammalian cells, and is found both in the cytoplasm and nucleus.…”