A Conserved Kinase-Based Body-Temperature Sensor Globally Controls Alternative Splicing and Gene Expression

Abstract

Highlights d CLK kinases are thermo-sensors reactive to subtle bodytemperature changes d Body temperature globally controls splicing and gene expression through CLKs d CLK homologs are evolutionarily adapted to diverse body/ growth temperatures d Wide functionality of CLKs: from TSD in reptiles to circadian biology in mammals

Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential

“…Interestingly, CLK1/4 activity is highly responsive to physiological temperature changes, which is caused by reversible temperature-dependent rearrangements in the kinase activation segment, reflected in temperature-dependent SR protein phosphorylation, splicing, and gene expression [ 71 ]. Specifically, it has been shown that lower body temperature causes activation of CLK1/4, which leads to increased SR protein phosphorylation.…”

Temperature-Dependent Alternative Splicing of Precursor mRNAs and Its Biological Significance: A Review Focused on Post-Transcriptional Regulation of a Cold Shock Protein Gene in Hibernating Mammals

“…A temperature change of 1 °C is sufficient to induce a concerted splicing switch in many genes that are functionally related to circadian rhythm. In addition, Haltenhof et al showed that a lower body temperature activates CDC-like kinases (CLKs), resulting in strongly increased phosphorylation of SR proteins [ 117 ]. This globally controls temperature-dependent alternative splicing and gene expression with wide implications in circadian, tissue-specific, and disease-associated settings [ 117 ].…”

Temperature does matter—an additional dimension in kinase inhibitor development

“…Recent work shows that the activity and/or specificity of at least two kinase families, p38alpha and CDC2like kinases (CLKs), is highly responsive to temperature changes in the physiological temperature range [7,8]. P38alpha belongs to the family of mitogen-activated kinases [9], whereas CLKs phosphorylate SR proteins, a family of proteins that control pre-mRNA processing, for example, alternative splicing [10].…”

“…Recent work has shown that circadian oscillations in core body temperature of only 1-2°C are sufficient to control CLK activity, which then alters the phosphorylation state of SR proteins and globally controls alternative splicing and gene expression [11,12]. This temperature-dependent change in CLK activity is mediated through subtle and reversible structural changes in the kinase activation segment, which in addition to controlling kinase activity is also involved in substrate binding and could thus alter substrate specificity and inhibitor binding [8]. Available CLK inhibitors have been identified in screens at 30°C or room temperature [13][14][15][16], whereas a screen at 37°C or 38°C, which induces the alternative conformation, has not been performed.…”