Abstract
Casein Kinase 1 epsilon (CK1ε) is a member of the serine (Ser)/threonine (Thr) CK1 family, known to have crucial roles in several biological scenarios and, ever more frequently, in pathological contexts, such as cancer. Recently, the human DEAD-box RNA helicase 3 X-linked (DDX3X), involved in cancer proliferation and viral infections, has been identified as one of CK1ε substrates and its positive regulator in the Wnt/β-catenin network. However, the way by which these two proteins influence each other has not been fully clarified. In order to further investigate their interplay, we defined the kinetic parameters of CK1ε towards its substrates: ATP, casein, Dvl2 and DDX3X. CK1ε affinity for ATP depends on the nature of the substrate: increasing of casein concentrations led to an increase of KmATP, while increasing DDX3X reduced it. In literature, DDX3X is described to act as an allosteric activator of CK1ε. However, when we performed kinase reactions combining DDX3X and casein, we did not find a positive effect of DDX3X on casein phosphorylation by CK1ε, while both substrates were phosphorylated in a competitive manner. Moreover, CK1ε positively stimulates DDX3X ATPase activity. Our data provide a more detailed kinetic characterization on the functional interplay of these two proteins.
Highlights
The casein kinase 1 (CK1) family is a group of multifunctional Ser/Thr-specific kinases ubiquitously expressed in eukaryotes, from yeasts to human, and involved in the regulation of several biological processes, such as cell proliferation and differentiation, chromosome segregation, DNA repair, cell survival and apoptosis, and the circadian rhythms [1,2,3,4,5]
Recent findings have reported that this kinase plays an important role in the induction of the well-known Wnt/β-catenin signaling cascade and, this role seems to be supported by its functional interaction with the ATP-dependent RNA helicase DDX3X, a multifunctional protein involved in several normal and pathological contexts, including viral infection and neoplastic transformation
Another study has revealed that the interplay between CK1ε and DDX3X has a role in the insurgence of neurodegenerative diseases, as in amyotrophic lateral sclerosis (ALS) [17]
Summary
The casein kinase 1 (CK1) family is a group of multifunctional Ser/Thr-specific kinases ubiquitously expressed in eukaryotes, from yeasts to human, and involved in the regulation of several biological processes, such as cell proliferation and differentiation, chromosome segregation, DNA repair, cell survival and apoptosis, and the circadian rhythms [1,2,3,4,5]. Many studies have shown that CK1 members phosphorylate about 50% of targets within the human phosphoproteome [9,10,11] For this reason, it is not surprising that various isoforms are involved in regulating and controlling many cellular processes, as well as that the deregulation of the activity of these enzymes was demonstrated to be associated with many disorders, including tumors and neurodegenerative diseases [8,12]. Deregulation of CK1ε has been reported in pathological conditions, such as several types of cancers and neurodegenerative diseases [12,15,16,17,18]
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