Abstract
BackgroundThe Mnk2 kinase, encoded by MKNK2 gene, plays critical roles in MAPK signaling and was involved in oncogenesis. Human MKNK2 pre-mRNA can be alternatively spliced into two splicing isoforms, the MKNK2a and MKNK2b, thus yielding Mnk2a and Mnk2b proteins with different domains. The involvement of Mnk2 alternative splicing in colon cancer has been implicated based on RNA-sequencing data from TCGA database. This study aimed at investigating the upstream modulators and clinical relevance of Mnk2 alternative splicing in colon adenocarcinoma (CAC).MethodsPCR, western blotting and immunohistochemistry (IHC) were performed to assess the expression of Mnk2 and upstream proteins in CAC. The function of Mnk2 and its regulators were demonstrated in different CAC cell lines as well as in xenograft models. Two independent cohorts of CAC patients were used to reveal the clinical significance of MKNK2 alternative splicing.ResultsComparing with adjacent nontumorous tissue, CAC specimen showed a decreased MKNK2a level and an increased MKNK2b level, which were correlated with KRAS mutation and tumor size. The SRSF1 (serine/arginine-rich splicing factor 1) was further confirmed to be the major splicing factor targeting MKNK2 in CAC cells. Higher expression of SRPK1/2 or decreased activity of PP1α were responsible for enhancing SRSF1 phosphorylation and nucleus translocation, subsequently resulted in a switch of MKNK2 alternative splicing.ConclusionsOur data showed that phosphorylation and subcellular localization of SRSF1 were balanced by SRPK1/2 and PP1α in CAC cells. High nucleus SRSF1 promoted MKNK2 splicing into MKNK2b instead of MNK2a, consequently enhanced tumor proliferation.
Highlights
IntroductionThe MAP kinase-interacting serine/threonineprotein kinase (Mnk) kinase, encoded by MKNK2 gene, plays critical roles in MAPK signaling and was involved in oncogenesis
The Mnk2 kinase, encoded by MKNK2 gene, plays critical roles in MAPK signaling and was involved in oncogenesis
TP53 seemed to have no impact on MKNK2 mRNA levels, MKNK2a splicing was inhibited while MKNK2b was remarkably upregulated in KRAS-mutated colon adenocarcinoma (CAC) samples
Summary
The Mnk kinase, encoded by MKNK2 gene, plays critical roles in MAPK signaling and was involved in oncogenesis. Human MKNK2 pre-mRNA can be alternatively spliced into two splicing isoforms, the MKNK2a and MKNK2b, yielding Mnk2a and Mnk2b proteins with different domains. This study aimed at investigating the upstream modulators and clinical relevance of Mnk alternative splicing in colon adenocarcinoma (CAC). Numerous well-known kinase networks are considered to play roles in CAC pathogenesis, such as EGFR, MAPKs, c-Src, et al The MAP kinase-interacting serine/ threonine-protein kinases (Mnks), downstream of MAPKs, are protein kinases that can phosphorylate eIF4E and enhance oncogenic mRNA translation [4]. Mnk2a and Mnk2b are two protein isoforms that derived from the MKNK2 pre-mRNA by alternative splicing, namely MKNK2a and MKNK2b, respectively [8]. Mnk2a directly interacts and phosphorylates p38α -MAPK, subsequently inducing cell death and suppressing Ras-induced transformation [10]. Mnk2b is generally recognized as a pro-oncogenic kinase due to its deficiency in binding p38α -MAPK but reserves capacity of phosphorylating eIF4E [10]
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