Good Cop, Bad Cop: The Different Roles of SRPKs

Abstract

SR Protein Kinases (SRPKs), discovered approximately 30 years ago, are widely known as splice factor kinases due to their decisive involvement in the regulation of various steps of mRNA splicing. However, they were also shown to regulate diverse cellular activities by phosphorylation of serine residues residing in serine-arginine/arginine-serine dipeptide motifs. Over the last decade, SRPK1 has been reported as both tumor suppressor and promoter, depending on the cellular context and has been implicated in both chemotherapy sensitivity and resistance. Moreover, SRPK2 has been reported to exhibit contradictory functions in different cell contexts promoting either apoptosis or tumor growth. The aim of the current review is to broaden and deepen our understanding of the SRPK function focusing on the subcellular localization of the kinases. There is ample evidence that the balance between cytoplasmic and nuclear SRPK levels is tightly regulated and determines cell response to external signals. Specific cell states coupled to kinase levels, spatial specific interactions with substrates but also changes in the extent of phosphorylation that allow SRPKs to exhibit a rheostat-like control on their substrates, could decide the proliferative or antiproliferative role of SRPKs.

Impaired expression of serine/arginine protein kinase 2 (SRPK2) affects melanoma progression

“…This finding supports the evidence that the increased malignant potential of melanoma cells, along with the consequent worsening in patient prognosis, should also be related to SRPK2 activity. Although the best-known function of SRPKs is classically related to regulation of pre-mRNA splicing (Wang et al, 1998), new findings have shown that these kinases can act broadly, depending on their expression levels and subcellular localization, the signaling pathways in which they are involved, and according to the cellular state (Nikolakaki et al, 2022). Here, we showed that genetic targeting of SRPK2 affected actin filament polymerization by decreasing the formation of F-actin in B16F10 cells.…”

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

“…Interestingly, Srpk3 overexpression in mice results in cardiomyopathy 16 , not seen in the KO model. Like RBM20, SRPKs exhibit strong spatiotemporal expression profiles 13 – 16 , and their subcellular localization is regulated by their own phosphorylation 53 and acetylation 54 , suggesting that these kinases are involved in tightly controlled and fine-tuned pathways at different developmental stages and in response to external signals 17 , 55 . While their role in mRNA regulation is well studied 13 , it has recently been shown that SRPKs are also involved in ubiquitin signaling 56 .…”

Chemo-phosphoproteomic profiling with ATR inhibitors berzosertib and gartisertib uncovers new biomarkers and DNA damage response regulators

“…Candidate kinases include those belonging to the SRPK family of kinases, which target serine residues which lie in SR motifs (88), and this will be interesting to investigate especially as to date these kinases have not been linked to maintenance of genome stability. Intriguingly, enrichment of non-overlapping phospho-motifs specific to each individual inhibitor was observed: YX[pS/pT] for berzosertib and pSXXXTP YXS/T for gartisertib.…”