About
Casein kinase 1 (CK1) is a family of serine/threonine protein kinases, which play essential regulatory functions in multiple cellular processes. These signalling kinases have been identified in most eukaryotes, from human to protozoa; they all share similar properties, including substrate recognition motifs. Defects in CK1 regulation, localisation or the occurrence of mutations within the CK1 coding sequence are associated with important human diseases such as cancer, neurodegenerative diseases or sleeping disorders. Therefore, CK1 family members have become interesting new drug targets, with each paralog having different therapeutic impact. There are also increasing evidence showing that manipulation of the host cell CK1 signalling pathways is common to many intracellular pathogens, through exploiting the host CK1 pathways (mycobacteria and viruses) or exporting directly their CK1 into the host cell (Leishmania and Plasmodium). These findings suggest that CK1 is a master regulator of intracellular pathogen survival and could greatly contribute to regulate host-pathogen interactions. This hypothesis is well illustrated by Leishmania. Leishmania casein kinase 1.2 (L-CK1.2) is released into the macrophages via extracellular vesicles, suggesting that it might have an important role for parasite survival in the mammalian hosts. We confirmed its ability to modify the proteome and phospho-proteome of macrophages in a cellular model, by interacting or phosphorylating host proteins. Moreover, we showed with the team of Professor Uwe Knippschild (Ulm University) that L-CK1.2 is regulated by a host up-stream kinase. We are currently comparing substrate phosphorylation by mammalian CK1 isoforms and L-CK1.2 and investigating the correlation between cancer and Leishmaniasis through CK1. To confirm these results in vivo and determine how CK1 is regulated in the host cell to compete with the host CK1s for substrates, the objectives of the project are: (1) to identify the host substrates phosphorylated by L-CK1.2, determine their importance for Leishmania infection; (2) to identify L-CK1.2-related peptides that specifically disrupt the interactions between this kinase and its selected substrates and test their efficiency to kill intracellular parasites; (3) characterise L-CK1.2 and huCK1δ regulation and affinity towards selected substrates; (4) to establish a link between the two teams through common lab meetings, the writing of common grant applications, technology transfers, and the organisation of a CK1 network.
