The casein kinase activity identified by Burnett et al. was subsequently found to be due to two distinct enzymes, casein kinase 1 and casein kinase 2. Subsequent research has shown that casein kinase 1 and casein kinase 2 (now referred to as CK1 and CK2 respectively), are in fact two families of evolutionarily unrelated Ser/Thr directed protein kinases. These kinase families have been extensively studied over the years and were found to regulate a variety of cellular processes.
Casein kinase 1 (CK1) was originally identified as the first of two kinases to elute from an anion exchange column with the ability to phosphorylate the acidic milk protein casein, thus the unfortunate moniker casein kinase 1. Over 2 decades later, numerous studies focusing on CK1 have provided insights into the substrate recognition motif, crystal structure, regulation of kinase activity, and subcellular localization, and identified potential in vivo functions for CK1 based on in vitro substrates. Studies in yeast have illuminated a role for CK1 in DNA repair, vesicle transport, and receptor internalization. As summarized in this review, a number of recent studies have provided compelling evidence for CK1 as a key regulator of several critical in vivo processes in metazoans.
The CK1 Family in Cell Signaling
Casein kinase 1 encompasses a large family of monomeric serine/threonine protein kinases. CK1 family members are found in a variety of subcellular locations including the nucleus, cytoplasm, cytoskeleton, vesicles, and the plasma membrane. In mammals, seven isoforms have been characterized, ranging in size from ≈30 to 60 kDa. Comparison with other kinase families reveal CK1 to be unique, with no closely related kinases. Thus far, seven mammalian CK1 isoforms have been identified (α, β, γ1, γ2, γ3, δ and ε), All isoforms have strongly conserved kinase domains while having variable amino (N) and carboxy (C) -terminal domains. Several splice variants have also been discovered for CKlα, CKlγ3, and CKlε, In the case of CKlα, splicing leads to the insertion of a long (28 a.a) or short (12 a.a) insert into the catalytic domain and generates four different splice products. These products have been shown to differ in their functions and cellular localization.
Members of the family are ubiquitously expressed and have been shown to be constitutively active. The constitutive activity is attributed to the continuous dephosphorylation of the Cterminal inhibitory domain by cellular phosphatases, It is speculated that subcellular localization in various cellular compartments may also play an important role in the regulation of CK1 kinase activity. Characterization of identified CK1 substrates and the use of peptide libraries has led to the identification of the consensus CK1 phosphorylation site as (pS)/(pT)- XX-S/T. This clearly indicates the preference of CK1 for a priming phosphorylation event by another kinase. Subsequent studies have shown that a cluster of acidic amino acids flanking the n-3 position can effectively substitute the requirement for a priming phosphorylation event.
CK1 substrates play roles in a multitude of cellular processes in mammals, ranging from membrane transport, cell cycle progression to apoptosis. In yeast, where several studies with the CK1 homologue have been performed, it has been shown to regulate membrane transport, cell morphology and DNA repair pathways. Use of CK1 inhibitors, including the highly specific kinase inhibitor D4476, has provided insights into the role of CK1 in mammalian cells. CK1 inhibitors have been shown to sensitize tumor cells to TRAIL induced apoptosis and modulate apoptosis induction by the Bid protein. The CK1 family is also a critical regulator of developmental pathways like the Wnt and Hedgehog signaling pathways, The best characterized role for the CK1 kinase family though, is in the regulation of mammalian circadian rhythms.
Naval P. Shanware. Regulation of DNA Damage Signaling and Circadian Rhythms by the Casein Kinase 1 Family of Proteins