ABOUT | mark2

MARK2, also known as Par-1b or EMK, is an isoform of the MARK enzyme. There are 4 MARK isoforms in humans. They are closely related to the AMP-activated protein kinase (AMPK) subfamily and together with other AMPK-like kinases, form the AMPK subgroup of the calcium/calmodulin-dependent protein kinase (CAMK) group of kinases. All MARK isoforms have similar domain organisation. They contain an N-terminal header, a catalytic kinase domain, linker, UBA domain, spacer and a tail domain [1]. MARK2 in humans has 788 residues [2]. It is activated by phosphorylation at the threonine 208 site in the activation loop by MARKK and LKB1. Phosphorylation of the residue at the serine 212 site by GSK3β inhibits MARK kinase activity [1] (Figure 1).

An introduction to MARK2

MARK2 regulates the dynamic instability of microtubules in cells by phosphorylating microtubule-associated proteins (MAPs). By phosphorylating MAPs, it blocks the interaction between MAPs and the microtubules, causing the detachment of MAPs from microtubules and decreasing the stability of microtubules in vitro [3]. In a study done by G. Drewes et al., Chinese hamster ovary (CHO) cells overexpressing MARK2 showed a dramatic loss in microtubules and were observed to be small, rounded and not viable [3]. MARK2 plays a role in the organisation of microtubules, establishment of cell polarity, cell migration, transport and neurodegeneration [4] [5].

MARK2 is essential in axon formation and neuronal migration and plays a role in neurodegenerative diseases like Alzheimer’s disease. Tau proteins are MAPs that regulates the assembly and stability of microtubules in the axons of neuronal cells [6]. Tau protein tangles, one of the hallmarks of Alzheimer’s disease, were shown to have lost their microtubule binding activity [2]. MARK2 phosphorylates tau proteins at particular sites (Figure 1), which causes tau to lose its microtubule stabilising activity, resulting in the breakdown of microtubules. The loss of the microtubule network disrupts axonal transport, causing the death of neurons and subsequently leads to neurodegeneration.

Figure 1. MARK2 enzymes are activated by phosphorylation of the threonine residue at the T208 site by MARKK and LKB1. It is inactivated by phosphorylation of the serine residue at the S212 site by GSK3β. These sites are located in the catalytic domain of MARK. An activated MARK2 enzyme can phosphorylate Tau and reduce its microtubule binding activity (A. Marx et al., 2010) [1].

MARK2 can selectively phosphorylate up to 8 serine residues on tau. Phosphorylation at the KXGS motifs, which contain the microtubule-binding domains, strongly reduces the interaction between tau and the microtubules [6].

PTEN-induced kinase 1 (PINK1) is a mitochondrial targeted serine/threonine kinase that promotes cell survival under oxidative or metabolic stress and is involved in the regulation of mitochondrial transport. MARK2 phosphorylates PINK1, usually at the threonine 313 site which lies in the catalytic domain. This increases its kinase activity and stabilises the mitochondrial transport-complex [7]. The failure of the MARK2-PINK1 signalling cascade is the cause of some variants of Parkinson’s disease. In these variants, mutation of the residue at the threonine 313 site in PINK1 to a non-phosphorylatable form results in abnormal mitochondrial distribution in neurons [4].

MARK2 has also been found to have an effect on glucose metabolism and obesity. MARK2 knockout mice are lean and resistant to weight-gain when placed on a high-fat diet. They also display an increase in insulin sensitivity as well as glucose uptake in adipose tissue [8].

REFERENCES

1 A. Marx, C. Nugoor, S. Paneerselvam, E. Mandelkow, 2010. Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases. The FASEB Journal, 24(6): 1637-48,

http://www.ncbi.nlm.nih.gov/pubmed/20071654

2 Serine/threonine kinase MARK2 isoform d (Homo sapiens)

http://www.ncbi.nlm.nih.gov/protein/254028234

3 G. Drewes, A. Ebneth, U. Preuss, E. M. Mandelkow, E. Mandelkow, 1997. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell, 89(2): 297-308,

http://www.ncbi.nlm.nih.gov/pubmed/9108484

4 D. Matenia, C. Hempp, T. Timm, A. Eikhof and E. M. Mandelkow, 2012. Microtubule affinity-regulating kinase 2 (MARK2) turns on phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) at Thr-313, a mutation site in Parkinson disease: effects on mitochondrial transport. Journal of Biochemistry, 287(11):8174-86,

http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=22238344

5 Y. Nishimura, K. Applegate, M. W. Davidson, G. Danuser, C. M. Waterman, 2012. Automated screening of microtubule growth dynamics identifies MARK2 as a regulator of leading edge microtubules downstream of Rac1 in migrating cells. PLos One, 7(7): e41413, http://www.ncbi.nlm.nih.gov/pubmed/22848487

6 M. Schwalbe, J. Biernat, S. Bibow, V. Ozenne, M. R. Jensen, H. Kadavath, M. Blackledge, E. Mandelkow, M. Zweckstetter, 2013. Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2. Biochemistry, 52(50):9068-9079

http://www.ncbi.nlm.nih.gov/pubmed/24251416

7 D. Matenia and E. M. Mandelkow, 2014. Emerging modes of PINK1 signalling: another task for MARK2. Frontiers in Molecular Neuroscience, 7:37,

http://www.ncbi.nlm.nih.gov/pubmed/24847206

8 J. B. Hurov, M. Huang, L. S. White, J. Lennerz, C. S. Choi, Y. R. Cho, H. J. Kim, J. L. Prior, D. Piwnica-Worms, L. C. Cantley, J. K. Kim, G. I. Shulman, H. Piwnica-Worms, 2007. Loss of the Par-1b/MARK2 polarity kinase leases to increased metabolic rate, decreased adiposity, and insulin hypersensitivity in vivo. Proceedings of the National Academy of Sciences of the United States of America, 104(13): 5680-5685,

http://www.ncbi.nlm.nih.gov/pubmed/17372192