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 4 (MARK4) was first described by Kato et al. (2001). MARK4 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 MARK4 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). MARK4 contains a ubiquitin-like domain adjacent to the kinase catalytic domain and undergoes Lys29/Lys33-linked polyubiquitylation that may inhibit its activity. It also interacts with the deubiquitylase USP9X (Al-Hakim et al., 2008).
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.
Kato T, Satoh S, et al. (2001) Isolation of a novel human gene, MARKL1, homologous to MARK3 and its involvement in hepatocellular carcinogenesis. Neoplasia 3, 4-9.
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.
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.