Abstract
Chemotherapeutic agents are frequently used to treat various cancers, but the mechanisms mediating the cellular response to the drugs are still not fully understood. We previously reported that the nuclear translocation of serine/arginine protein kinases (SRPKs), triggered by the exposure of cells to DNA damage-inducers, plays a pivotal role in drug responsiveness. Here, we investigated the mechanism linking the nuclear accumulation of SRPK2 to the cisplatin treatment of HeLa cells. We present experimental evidence that nuclear SRPK2 acts downstream of Chk2 in the ATM/Chk2 cascade. The inhibition of ATM or Chk2 kinase activity by specific low-molecular-weight inhibitors restricted SRPK2 to the cytoplasm and conferred tolerance to cisplatin treatment. A similar effect was achieved by treating cells with SRPIN340, a selective SRPK1/2 inhibitor, thus confirming previous findings that kinase activity is indispensable for the nuclear import of SRPKs. These data add to previous findings that support a decisive role of SRPKs in coordinating cellular response to DNA damage.
Highlights
Ke Ding and Dandan SunThe serine/arginine protein kinases (SRPKs) family of protein kinases is highly conserved throughout eukaryotes [1].SRPKs were initially considered to phosphorylate the RS domains of SR splicing factors, thereby regulating pre-mRNA splicing [1]
To determine whether there was a link between translocation to the nucleus and the phosphorylation of SRPK1, we showed that 5-FU treatment triggered the phosphorylation of two residues within the spacer domain of the kinase, Thr326 and Ser408, in an ATR/ATM-dependent manner
The treatment of HeLa cells with cisplatin caused a significant relocation of SRPK2 to the nucleus [8], implying that distinct signaling pathways are activated in response to 5-FU and cisplatin
Summary
Ke Ding and Dandan SunThe SRPK family of protein kinases is highly conserved throughout eukaryotes [1].SRPKs were initially considered to phosphorylate the RS domains of SR splicing factors, thereby regulating pre-mRNA splicing [1]. Several non-splicing functions of SRPKs have been reported, and these could be ascribed to the phosphorylation of various substrates involved in multiple cellular processes [1,2]. Both SRPK1 and SRPK2 are predominantly localized in the cytoplasm of cancer cells, and they contain two conserved kinase domains that are interrupted by a unique spacer sequence. SRPK1 undergoes cytoplasmic-to-nuclear relocation by removing the spacer sequence, and this translocation may lead to effects including the alteration of splice site selection, the aggregation of splicing factors, and severe splicing defects [3,4]. The effects were found to be even more harmful in budding yeast, where the mis-localization of Sky
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