Background
Protein ubiquitylation and protein phosphorylation are the two major mechanisms that regulate the functions of proteins in eukaryotic cells. However, these different posttranslational modifications do not operate independently of one another, but are frequently interlinked to enable biological processes to be controlled in a more complex and sophisticated manner. Studying how protein phosphorylation events control the ubiquitin system and how ubiquitylation regulates protein phosphorylation has become a focal point of the study of cell regulation and human disease. Cloning of human Microtubule Affinity Regulating Kinase 3 (MARK3) was first described by Peng et al. (1998). MARK3 is a member of the subfamily of protein kinases that include the AMP-activated protein kinase (AMPK) and, like AMPK itself, is activated by the tumour suppressor kinase LKB1 (Lizcano et al., 2004). The physiological roles of the MARK subfamily of protein kinases include the phosphorylation of microtubule associated proteins and the regulation of cell polarity. Members of the MARK sub-family also phosphorylate tau at sites that induce its dissociation from tubulin. Enhanced phosphorylation of these sites is an early hall mark of Alzeheimer's disease and is followed by abnormal aggregation of tau to paired helical filaments that are found in people with Alzheimer's disease (Marx et al., 2010). MARK3 contains a ubiquitin-like domain adjacent to the kinase catalytic domain and, similar to MARK4, undergoes Lys29/Lys33-linked polyubiquitylation that may inhibit its activity. It may also interact with the deubiquitylase USP9X (Al-Hakim et al., 2008).
References
Al-Hakim AK, Zagorska A, Chapman L, Deak M, Peggie M, Alessi DR (2008) Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains. Biochem J 411, 249-60.
Hastie CJ, McLauchlan HJ, Cohen P (2006) Assay of protein kinases using radiolabeled ATP: a protocol. Nat Protoc 1, 968-71.
Lizcano JM, Goransson O, et al. (2004) LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J 23, 833-43.
Marx A, Nugoor C, Panneerselvam S, Mandelkow E (2010) Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases. FASEB J 24, 1637-48.
Peng CY, Graves PR, Ogg S, Thoma RS, Byrnes MJ, 3rd, Wu Z, Stephenson MT, Piwnica-Worms H (1998) C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Cell Growth Differ 9, 197-208.
Background kindly written by:
Sir Philip Cohen FRS, FRSE
University of Dundee
Director of the Medical Research Council Protein Phosphorylation Unit (1990-2012)
Director of the Scottish Institute for Cell Signalling incorporating the Protein Ubiquitylation Unit (2008-2012)
Co-Director of the Division of Signal Transduction Therapy (1998-2012)
Deputy Director of the Division of Signal Transduction Therapy (from July 2012)
Professor Cohen's research group is studying the interplay between protein phosphorylation and protein ubiquitylation in the regulation of innate immunity.