Connecting the speckles: Splicing kinases and their role in tumorigenesis and treatment response

Corkery, Dale; Holly, Alice C.; Lahsaee, Sara; Dellaire, Graham

doi:10.1080/19491034.2015.1062194

Cited by 67 publications

(75 citation statements)

References 126 publications

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“…In response to feeding, CLK2 is stabilized by Akt activation and directly hyperphosphorylates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) at the SR domain to repress its activity toward target genes (Rodgers et al, 2010). CLK2 has also been reported to play a role in SR protein recruitment and pre-mRNA splicing (Corkery et al, 2015). In addition, hepatic CLK2 interacts with regulatory subunits of the protein phosphatase 2A (PP2A) complex.…”

Section: Introductionmentioning

confidence: 99%

Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting

et al. 2017

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Summary A promising approach to treating obesity is to increase diet-induced thermogenesis in brown adipose tissue (BAT), but the regulation of this process remains unclear. Here, we find that CDC-like kinase 2 (CLK2) is expressed in BAT and upregulated upon refeeding. Mice lacking CLK2 in adipose tissue exhibit exacerbated obesity and decreased energy expenditure during high fat intermittent fasting. Additionally, tissue oxygen consumption and protein levels of UCP1 are reduced in CLK2-deficient BAT. Phosphorylation of CREB, a transcriptional activator of UCP1, is markedly decreased in BAT cells lacking CLK2 due to enhanced CREB dephosphorylation. Mechanistically, CREB dephosphorylation is rescued by inhibition of PP2A, a phosphatase that targets CREB. Our results suggest that CLK2 is a regulatory component of diet-induced thermogenesis in BAT through increased CREB-dependent expression of UCP1.

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Section: Introductionmentioning

confidence: 99%

Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting

et al. 2017

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“…In contrast, KKT10 and KKT19, which have a CLK-like kinase domain, localize at kinetochores from S phase until the onset of anaphase. In other eukaryotes, CLK kinases are implicated in RNA splicing (Corkery et al, 2015), not kinetochore functions, suggesting that KKT10/19 likely evolved from a CLK kinase to carry out distinct functions in kinetoplastids.…”

Section: Discussionmentioning

confidence: 99%

Unconventional kinetochore kinases KKT10/19 promote the metaphase to anaphase transition in Trypanosoma brucei

Ishii

Akiyoshi

2019

Preprint

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Trypanosoma brucei has unique kinetochore proteins and lacks a canonical spindle checkpoint system. How mitotic progression is regulated in this organism remains unclear.Here we show that two redundant protein kinases KKT10/19 promote the metaphase to anaphase transition. AbstractThe kinetochore is a macromolecular protein complex that drives chromosome segregation in eukaryotes. Unlike most eukaryotes that have canonical kinetochore proteins, evolutionarily divergent kinetoplastids such as Trypanosoma brucei have unconventional kinetochore proteins. T. brucei also lacks a canonical spindle checkpoint system and it therefore remains unknown how mitotic progression is regulated in this organism. Here we characterized two paralogous kinetochore proteins with a CLK-like kinase domain, KKT10 and KKT19, which localize at kinetochores in metaphase but disappear at the onset of anaphase. We found that these proteins are functionally redundant. Double knockdown of KKT10/19 led to a significant delay in the metaphase to anaphase transition. A kinase-dead mutant of KKT10 failed to rescue the KKT10/19 depletion phenotype, suggesting that its 2 kinase activity is essential. We also found that phosphorylation of two kinetochore proteins KKT4 and KKT7 depends on KKT10/19 in vivo. Finally, we showed that the N-terminal part of KKT7 directly interacts with KKT10 and that kinetochore localization of KKT10 depends not only on KKT7 but also on the KKT8 complex. Our results reveal that kinetochore localization of KKT10/19 is tightly controlled to regulate the metaphase to anaphase transition in T. brucei.

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“…These reports suggest important sex-specific differences resulting from mutations in SRPK3. Finally, while SRPK1 and SRPK2 have been studied in many cancers (69), the roles of SRPK3 and its importance as a biomarker have not been delineated in human cancer.…”

Section: Immature B Cells Represent a Key Checkpoint In Bone Marrow Bmentioning

confidence: 99%

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

Arends

Taliaferro

Peterman

et al. 2019

Preprint

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One Sentence Summary: SRPK3 regulates alternative splicing of pre-mRNA that is crucial for B cell development, activation and antibody responses. Abstract:Alternative splicing (AS) of pre-mRNA is a critical component of transcriptional regulation that diversifies the cellular proteome. The Serine-Arginine Protein Kinases (SRPK) initiate early events in AS. Using conditional knockout mice (cKO), we demonstrated the importance of the X-linked gene Srpk3 in B lymphocyte development and in response to immunization in vivo.Significantly decreased numbers of immature and mature B cells were observed in Srpk3-cKO BM relative to wild-type (WT). Immunization of Srpk3-cKO mice with a T lymphocyteindependent type-2 antigen elicited greatly reduced amounts of specific IgG3. Srpk3 deletion resulted in hundreds of differentially spliced mRNAs in B cells, including mRNAs encoding proteins associated with signaling pathways and mitochondrial function. Several alternative splicing outcomes in Srpk3-cKO cells are due to altered splicing regulation of SR proteins. We conclude that Srpk3 is an immunomodulatory kinase that controls humoral immunity via its regulation of pre-mRNA splicing, antibody production, and metabolism in B cells. Introduction:Co-transcriptional mechanisms of gene regulation are emerging as important contributors to immune cell differentiation and function. One such mechanism is alternative pre-mRNA splicing (AS), which increases informational diversity, functional capacity, and the efficiency of protein expression (1). Recent studies have confirmed that AS influences immunity and tolerance through its roles in lymphocyte homeostasis (2). Additionally, B cell differentiation, activation, and maturation to antigen secreting cells (ASCs) are dependent on unique splicing patterns that modulate B cell responsiveness and function (3,4). Therefore, understanding how pre-mRNA splicing is regulated in these cells is of critical importance.The functional spliceosome is a dynamic machine comprised of approximately 20 protein and RNA components that regulate splice site selection in pre-mRNAs concurrently with transcription (5, 6). Upstream regulators of splicing include the Serine-Arginine Protein Kinase (SRPK) family, a group of highly conserved serine-threonine kinases that phosphorylate Serine-Arginine repeat (SR)-rich proteins in response to extracellular signals (7-10). SR proteins include splicing factors (SRSF1-12) that promote splice site selection by bridging between initial splice site selection in the pre-spliceosome and assembly of the mature spliceosome.In mammals, SRPK proteins (SRPK1 and SRPK2) have been extensively studied as regulators of AS and mRNA maturation (11-13), transduction of growth signaling (14), chromatin reorganization (15), cell cycle (7) and metabolic signaling (16). However, the function of SRPK3 has not been elucidated. SRPK3 was identified first as a transcriptional target of Myocyte Enhancer Factor 2C (MEF2C) in skeletal muscle and the heart (17). Later studies identified the X-linked ...

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Connecting the speckles: Splicing kinases and their role in tumorigenesis and treatment response

Cited by 67 publications

References 126 publications

Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting

Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting

Unconventional kinetochore kinases KKT10/19 promote the metaphase to anaphase transition in Trypanosoma brucei

SRPK3 regulates alternative pre-mRNA splicing required for B lymphocyte development and humoral responsiveness

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