Casein Kinase Substrates

Definition

Casein kinases are Ser/Thr protein kinases that have been implicated in cell cycle control, circadian rhythm, DNA repair and other cellular processes1. Several substrates of casein kianses have been identified and even synthesized artificially2.

Discovery

Casein kinase activity associated with the endoplasmic reticulum of mammary glands was first characterized in 19743.

Classification

Casein kinase belongs to the kinase family of proteins and its substrates that are proteins involved in various cellular processes are numerous in number. Two casein kinases have been widely studied: Casein kinase I and II3.

Structural Characteristics

The substrate for casein kinase I has the sequence motif –S(P)XXS-. The phosphorylated serine is known to be an effective substrate for the kinase4. Similarly the synthetic peptide, Arg-Arg-Arg-Glu-Glu-Glu-Thr-Glu-Glu-Glu serves as an effective substrate for casein kinase II5. In cells, substrates of casein kinase II have been found to have Leu-zipper motifs6.

Mode of action

Casein kinase I substrates bind to the active site of the kinase monomer where they are phosphorylated7. Casein kinase II normally binds to the leucine-zipper DNA binding domain of proteins6.

Functions

Casein kinase I substrates are involved in RNA metabolism (helicases and ribosomal proteins), glycogen metabolism (glycogen synthase), tumor suppression (p53), transcription (CREM), DNA repair and cell morphogenesis2. Casein kinase II substrates are mainly transcription factors (cMyc, cJun, cMyb), cofactors (PC4), basal factors (TFIIIB), viral transactivators (adenovirus E1A) and glycogen metabolism (glycogen synthase)6.

References


1. Burnett G and Kennedy E (1954). The enzymatic phosphorylation of proteins. J Biol. Chem., 211, 969-80.

2. Gao ZH., Metherall J., Virshup DM (2000). Identification of casein kinase I substrates by in vitro expression cloning screening. Biochem. and Biophy. Res. Comm., 268 (2), 562-66.

3. Bingham E and Farrel H (1974). Casein kinase from the Golgi apparatus of lactating mammary gland. J Biol.Chem., 249, 3647-51.

4. Flotow H and Roach P (1991). Role of Acidic Residues as Substrate Determinants for Casein Kinase I. J Biol. Chem., 266(6), 3724-27.

5. Kuenzel EA and Krebs EG (1995). A synthetic peptide substrate specific for casein kinase II (protein kinase/protein kinase specificity/peptide phosphorylation). Proc. Natl. Acad. Sci., 82, 737-41.

6. Yamaguchi Y, Wada T, Suzuki F, Takagi T, Hasegawa J, and Handa H (1998). Casein kinase II interacts with the bZIP domains of several transcription factors. Nucleic Acids Res, 26(16), 3854–3861.

7. Xu RM, Carmel G, Sweet RM, Kuret J, and Cheng X (1995). Crystal structure of caseinkinase-1, a phosphate-directed protein kinase. EMBO J, 14(5), 1015–1023.