Project Knippschild

CK1 signalling and apoptosis
(Uwe Knippschild, Institute General-, Visceral-, and Transplantation Surgery)

PD Dr. Uwe Knippschild
Institute General-, Visceral-, and Transplantation Surgery
Ulm University
Steinhövelstr. 9
D-89075 Ulm

Members of the casein kinase 1 (CK1) family are highly conserved and are expressed in many eukaryotes ranging from yeast to humans. Mammalian CK1 isoforms (alpha, beta, gamma, delta, epsilon)  and their splice variants are involved in diverse cellular processes, including membrane trafficking, circadian rhytmns, cell cycle progression, chromosome segregation, apoptosis and cellular differentiation. Mutations and deregulation of CK1 expression and activity has been linked to various diseases, including neurodegenerative disorders, like Alzheimer and Parkinson, sleeping disorders, and proliferative diseases, like cancer. Therefore, interest in specifically targeting members of the CK1 family for drug development has increased. To establish new therapy concepts, especially in cancer treatment, a great challenge will be the generation of inhibitors either inhibiting specifically one of the CK1 isoforms or a specific interaction of one CK1 isoform with a defined substrate without affecting its ability to phosphorylate and interact with key regulator proteins of other cellular pathways.

CK1 activity has been shown to be tightly regulated. Extracellular stimuli, their subcellular localization, their interaction with various cellular structures and cellular proteins, as well as autophosphorylation and proteolytic cleavage of their C-terminal regulatory domains influence the activity of mammalian CK1 isoforms. The aim of the proposed project is the identification of cellular factors modulating the activity, substrate-specificity and functions of CK1 using biochemical, cell biology and molecular biology techniques. Factors being able to downregulate the antiapoptotic functions of CK1 are of special interest.

Selected publications

Rewiews

Knippschild, U., Gocht, A., Wolff, S., Huber, N., Lohler, J. and Stoter, M. (2005). The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell Signal 17, 675-89.

 Knippschild, U., Wolff, S., Giamas, G., Brockschmidt, C., Wittau, M., Wurl, P. U., Eismann, T. and Stoter, M. (2005). The role of the casein kinase 1 (CK1) family in different signaling pathways linked to cancer development. Onkologie 28, 508-14.

Meek, D. W. and Knippschild, U. (2003). Posttranslational modification of MDM2. Mol Cancer Res 1, 1017-26.

Orginal papers

Wolff, S., Xiao, Z., Wittau, M., Sussner, N., Stoter, M. and Knippschild, U. (2005). Interaction of casein kinase 1 delta (CK1delta) with the light chain LC2 of microtubule associated protein 1A (MAP1A). Biochim Biophys Acta 1745, 196-206.

Stoter, M., Bamberger, A. M., Aslan, B., Kurth, M., Speidel, D., Loning, T., Frank, H. G., Kaufmann, P., Lohler, J., Henne-Bruns, D., Deppert, W. and Knippschild, U. (2005). Inhibition of casein kinase I delta alters mitotic spindle formation and induces apoptosis in trophoblast cells. Oncogene 24, 7964-75.

Winter, M., Milne, D., Dias, S., Kulikov, R., Knippschild, U., Blattner, C. and Meek, D. (2004). Protein kinase CK1delta phosphorylates key sites in the acidic domain of murine double-minute clone 2 protein (MDM2) that regulate p53 turnover Biochemistry 43, 16356-64.

Ventura, R. A., Martin-Subero, J. I., Knippschild, U., Gascoyne, R. D., Delsol, G., Mason, D. Y. and Siebert, R. (2004). Centrosome abnormalities in ALK-positive anaplastic large-cell lymphoma. Leukemia 18, 1910-1.

Maritzen, T., Lohler, J., Deppert, W. and Knippschild, U. (2003) Casein kinase I delta (CKIdelta) is involved in lymphocyte physiology. Eur J Cell Biol 82, 369-78.

Martin-Subero, J. I., Knippschild, U., Harder, L., Barth, T. F., Riemke, J., Grohmann, S., Gesk, S., Hoppner, J., Moller, P., Parwaresch, R. M. and Siebert, R. (2003). Segmental chromosomal aberrations and centrosome amplifications: pathogenetic mechanisms in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma? Leukemia 17, 2214-9.

Behrend, L., Stoter, M., Kurth, M., Rutter, G., Heukeshoven, J., Deppert, W. and Knippschild, U. (2000). Interaction of casein kinase 1 delta (CK1delta) with post-Golgi structures, microtubules and the spindle apparatus. Eur J Cell Biol 79, 240-51.

Behrend, L., Milne, D. M., Stoter, M., Deppert, W., Campbell, L. E., Meek, D. W. and Knippschild, U. (2000). IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects. Oncogene 19, 5303-13.

Knippschild, U., Milne, D. M., Campbell, L. E., DeMaggio, A. J., Christenson, E., Hoekstra, M. F. and Meek, D. W. (1997). p53 is phosphorylated in vitro and in vivo by the delta and epsilon isoforms of casein kinase 1 and enhances the level of casein kinase 1 delta in response to topoisomerase-directed drugs. Oncogene 15, 1727-36.