MARK2

MARK2 homologues are present in various species, including humans, mice, African clawed frogs, monkeys and zebrafish. The major functions of MARK2 are conserved across the species. This includes transport, migration, regulating the organisation of cytoskeletal elements, and acting in the establishment and maintenance of cell polarity in neurons and epithelial cells. Phosphorylation targets include TORC2, DCX, MAP2, MAP4, MAPT, RAB11 and kinesin-like protein KIF13B. It has various binding capabilities; as well as binding to magnesium ions, ATP and protein, MARK2 can bind lipids and poly (A) RNA.

 

Flat file #1: MARK2, Homo sapiens

 

The longest isoform of the human MARK2 protein is 788 amino acids long. It is activated by phosphorylation at Thr208 and inhibited by phosphorylation at Ser212 and Thr596. MARK2 binds to the N-terminal tail of the human Tau protein and phosphorylates three major and five minor serine residues in the repeat domain and C-terminal tail of the structure [1]. Human MARK2 has been additionally identified as a regulated target downstream of Rac1 that is required in the directional growth of microtubules to mediate cell migration [2]. The human MARK2 gene is found on chromosome 11.

 

Flat file #2: MARK2, Mus musculus

 

Isoform 1 of Mouse MARK2 is 776 amino acids long. It is activated by phosphorylation at Thr208 and inhibited by phosphorylation at Ser-212 and Thr-593. Localisation of MARK2 to the basolateral membrane is required in the establishment of cell polarity during early mouse embryogenesis [3]. As well as functioning in regulation of microtubules and the maintenance of cell polarity, the MARK2 protein in mice plays a role in glucose metabolism. Defects in MARK2 can lead to hypersensitivity to insulin and an increased metabolic rate [4]. The mouse MARK2 gene is found on chromosome 19.

 

Flat file #3: MARK2, Xenopus laevis

 

The African clawed frog MARK2 equivalent is 780 amino acids long. In addition to the functions listed above, it is involved in a regulatory step, along with the protein Dishevelled, in transforming growth factor beta (TFG-β) and bone morphogenetic protein (BMP) signalling in Xenopus laevis mesoderm development [5].

 

Flat file #4: MARK2, Rattus norvegicus

 

MARK2 in the Norway rat, the original MARK2 protein first identified, is 722 amino acids long. It acts as an upstream regulator of phosphatase and tensin homolog (PTEN)-induced kinase 1 at Thr313, a mutation site in Parkinson disease [6]. It is activated by phosphorylation on Thr208 and inhibited by phosphorylation at Ser212 or Thr539. Phosphorylation at Thr539 by protein PRKCZ/aPKC and the subsequent interaction with 14-3-3 protein YWHAZ promotes the relocation of MARK2 from the cell membrane to the cytoplasm. The Rattus norvegicus MARK2 gene is found on chromosome 1.

 

Flat file #5: MARK2, Bos Taurus

 

The MARK2 protein in cattle is 691 amino acids long. The gene is encoded on chromosome 29.

 

References

1. Schwalbe M, Biernat J, Bibow S, Ozenne V, Jensen MR, Kadavath H, Blackledge M, Mandelkow E, and Zweckstetter M. (2013). Phosphorylation of human Tau protein by microtubule affinity-regulating kinase 2. Biochemistry. 52:9068-79.

2. Nishimura Y, Applegate K, Davidson MW, Danuser G and Waterman CM . (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:e41413.

3. Tao H, Inoue K, Kiyonari H, Bassuk AG, Axelrod JD, Sasaki H, Aizawa S and Ueno N. (2012). Nuclear localization of Prickle2 is required to establish cell polarity during early mouse embryogenesis. Developmental Biology. 364:138–148

4. Hurov JB, Huang M, White LS, Lennerz J, Choi CS, Cho YR, Kim HJ, Prior JL, Piwnica-Worms D, Cantley LC, Kim JK, Shulman GI and Piwnica-Worms H. (2007). Loss of the Par-1b/MARK2 polarity kinase leads to increased metabolic rate, decreased adiposity, and insulin hypersensitivity in vivo. PNAS. 104:5680-5.

5. Mamidi A, Inui M, Manfrin A, Soligo S, Enzo E, Aragona M, Cordenonsi M, Wessely O, Dupont S and Piccolo S.(2012). Signaling crosstalk between TGFβ and Dishevelled/Par1b. Cell Death & Differentiation. 19:1689-97.

6. Matenia D, Hempp C, Timm T, Eikhof A and Mandelkow EM. Microtubule Affinity-regulating Kinase 2 turns on phosphatase and tensin homolog (PTEN)-induced Kinase 1 (PINK1) at Thr-313, a mutation site in Parkinson Disease. The Journal of Biological Chemistry. 287:8174-86.