Tinker, Tailor, Tumour Suppressor: The Many Functions of PRP4K

Abstract

Pre-mRNA processing factor 4 kinase (PRP4K, also known as PRPF4B) is an essential kinase first identified in the fission yeast Schizosaccharomyces pombe that is evolutionarily conserved from amoebae to animals. During spliceosomal assembly, PRP4K interacts with and phosphorylates PRPF6 and PRPF31 to facilitate the formation of the spliceosome B complex. However, over the past decade additional evidence has emerged that PRP4K has many diverse cellular roles beyond splicing that contribute to tumour suppression and chemotherapeutic responses in mammals. For example, PRP4K appears to play roles in regulating transcription and the spindle assembly checkpoint (SAC), a key pathway in maintaining chromosomes stability and the response of cancer cells to taxane-based chemotherapy. In addition, PRP4K has been revealed to be a haploinsufficient tumour suppressor that promotes aggressive cancer phenotypes when partially depleted. PRP4K is regulated by both the HER2 and estrogen receptor, and its partial loss increases resistance to the taxanes in multiple malignancies including cervical, breast and ovarian cancer. Moreover, ovarian and triple negative breast cancer patients harboring tumours with low PRP4K expression exhibit worse overall survival. The depletion of PRP4K also enhances both Yap and epidermal growth factor receptor (EGFR) signaling, the latter promoting anoikis resistance in breast and ovarian cancer. Finally, PRP4K is negatively regulated during epithelial-to-mesenchymal transition (EMT), a process that promotes increased cell motility, drug resistance and cancer metastasis. Thus, as we discuss in this review, PRP4K likely plays evolutionarily conserved roles not only in splicing but in a number of cellular pathways that together contribute to tumour suppression.

Moderate maternal nutrient reduction in pregnancy alters fatty acid oxidation and RNA splicing in the nonhuman primate fetal liver

“…These include TRA2B, MBNL1, CCNL2, RAVER1, the HNRNP family, and PRPF4B. 29,[37][38][39][40][41] On a less dramatic scale than loss of function mutations, we propose that the downregulation of these genes caused by decreased nutrient availability in the fetal liver may be the fetus' way of producing a wider variety of gene isoforms as a potential mechanism of environmental adaptation.…”

The evolutionarily conserved PRP4K-CHMP4B/vps32 splicing circuit regulates autophagy

“…The mis-splicing of genes in the ESCRT-III pathway in particular, CHMP2B and CHMP4B, are known to impact autophagy and play roles in the pathogenesis of cancer and neurological diseases 11,12,70 . Here we have identified a novel conserved role for PRP4K in regulating autophagosome-lysosome fusion via CHMP4B splicing, which has implications for understanding how inhibition or loss of splicing kinases may contribute to disease pathogenesis through impaired autophagy, including aggressive cancer phenotypes associated with loss of PRP4K 20 . buffer and harvested at the indicated timepoints to assess levels of Prp4k.…”

“…Although an essential gene in most eukaryotic organisms [18][19][20] , partial loss of PRP4K expression is common in multiple cancers, and is associated with epithelial-to-mesenchymal transition (EMT), mitotic defects, and anoikis resistance driven by enhanced epithelial growth factor receptor (EGFR) and Yes-associated protein (YAP) signalling [21][22][23][24][25] . These studies point to a broad tumour suppressor role for PRP4K 20 .…”

“…RNA interference knockdown (RNAi KD) models have been the primary tool for evaluating PRP4K function as this gene is essential in most eukaryotic models 20 . Here, we have identified a protist that can tolerate the loss of PRP4K, Dictyostelium discoideum ; an amoeba species that diverged from humans approximately 600 million years ago 26 .…”