PSF: nuclear busy-body or nuclear facilitator?

Abstract

PTB-associated splicing factor (PSF) is an abundant and essential nucleic acid-binding protein that participates in a wide range of gene regulatory processes and cellular response pathways. At the protein level, PSF consists of multiple domains, many of which remain poorly characterized. Although grouped in a family with the proteins p54nrb/NONO and PSPC1 based on sequence homology, PSF contains additional protein sequence not included in other family members. Consistently, PSF has also been implicated in functions not ascribed to p54nrb/NONO or PSPC1. Here, we provide a review of the cellular activities in which PSF has been implicated and what is known regarding the mechanisms by which PSF functions in each case. We propose that the complex domain arrangement of PSF allows for its diversity of function and integration of activities. Finally, we discuss recent evidence that individual activities of PSF can be regulated independently from one another through the activity of domain-specific co-factors.

Figure 1

Cellular activities of PTB‐associated splicing factor (PSF). A schematic highlighting the cellular activities which PSF has thus far been reported to regulate. Black activities are those for which the mechanism of PSF activity is best understood. Gray activities are those with less experimental support or unclear mechanism. Dotted double arrow indicates coordination of activities through PSF.

Figure 2

Domain structure of PTB‐associated splicing factor (PSF). A schematic of the domains of PSF along the primary sequence of the protein. Numbers indicate amino acid. Domains are as discussed in the text. RGG, RGG box; P, proline‐rich domain including proline/glutamine‐rich subdomain (P,Q); PRL, PR linker; NLS, nuclear‐localization sequence. RRM1, RRM2, NOPS, and coiled‐coil domains are as listed. The portion of PSF that comprises the DBHS core region is noted. Exact amino acid boundaries of the NLS are also given below.

Figure 3

Regulation of PTB‐associated splicing factor (PSF). (a) PSF protein partners. Arrows indicate approximate domain of PSF through which partner proteins interact, in the cases where this is known. Protein partners for which no domain information is available are listed to the top right. (b) Location of mapped sites of phosphorylation on PSF for which the kinase is known. Also shown are additional mapped sites of methylation (Me) and sumoylation (Sumo). (c) Schematic of one pathway of PSF regulation for which details are known. GSK3, PSF, and TRAP‐150 are as described in the text. PKC is protein kinase C, a signaling molecule known to induce inhibitory phosphorylation of GSK3, thereby reducing its activity. Red ‘P’ indicates GSK3‐dependent phosphorylation of PSF. Gray and beige boxes and lines correspond to the exons and introns of the CD45 gene. The central beige exon corresponds to CD45 exon 4, a known target of PSF repressive activity.