MARK2 (MAP/Microtubule Affinity-Regulating Kinase 2), also known as EMK1 or Par-1b, is a serine/threonine kinase that directly phosphorylates tau and other microtubule-associated proteins at KXGS motifs.[1][2] As a member of the AMPK-related kinase family, MARK2 plays critical roles in establishing neuronal polarity, regulating microtubule dynamics, and modulating axonal transport.[1:1] Dysregulated MARK2 activity has been implicated in Alzheimer's Disease, progressive supranuclear palsy, and other tauopathies.[2:1][3]
| Attribute | Value |
|---|---|
| Protein Name | MAP/Microtubule Affinity-Regulating Kinase 2 |
| Gene | MARK2 |
| UniProt ID | Q7KZI7 |
| Molecular Weight | ~80 kDa |
| Subcellular Localization | Cytoplasm, membrane, cell junctions |
| Protein Family | MARK/Par-1 kinase family |
MARK2 has a conserved multidomain architecture shared across the MARK kinase family (MARK1-4):
Crystal structures reveal that the UBA domain folds back onto the kinase domain in the inactive conformation, providing structural insight into how MARK2 transitions between active and autoinhibited states.[4:3]
MARK2 phosphorylates the KXGS motifs within the microtubule-binding repeats of tau (notably Ser262 and Ser356), MAP2, and MAP4.[1:4][2:2] This phosphorylation reduces MAP-microtubule binding affinity, increasing microtubule dynamic instability. This detachment mechanism is essential for microtubule remodeling during neuronal migration, axon branching, and synaptic plasticity.[1:5]
MARK2 is essential for establishing axon-dendrite polarity in developing neurons. In the LKB1-MARK polarity pathway, LKB1 activates MARK2, which then phosphorylates tau to locally destabilize microtubules in future dendritic processes while allowing the single axon to elongate.[5] Overexpression of MARK2 produces multiple axons, while kinase-dead MARK2 prevents axon specification.[5:1] The asymmetric distribution of MARK2 activity, regulated by Par3-Par6-aPKC signaling, creates the polarity break that defines neuronal morphology.[5:2]
By regulating the attachment of MAPs to microtubules, MARK2 indirectly controls the efficiency of kinesin- and dynein-mediated axonal transport.[1:6] Excessive MARK2 activity strips MAPs from microtubule tracks, impairing cargo motility — a mechanism directly relevant to axonal transport failure in neurodegeneration.
Phosphorylation of tau at Ser262 by MARK kinases is among the earliest detectable tau modifications in AD brain and is thought to be a priming event that precedes phosphorylation at downstream sites by GSK-3β and CDK5.[2:3][3:1] The Ser262 site lies within the first microtubule-binding repeat and its phosphorylation alone reduces tau-microtubule binding by approximately 80%.[2:4] In Drosophila tauopathy models, mutating the MARK-targeted KXGS sites to non-phosphorylatable alanines completely blocks tau toxicity, demonstrating that MARK-mediated phosphorylation is necessary (not merely correlative) for tau-induced neurodegeneration.[6] MARK2 expression is upregulated in AD hippocampus, and MARK2 colocalizes with pre-tangle tau in early Braak stage neurons.[3:2]
In PSP and corticobasal degeneration, MARK-phosphorylated tau epitopes (detected by the 12E8 antibody against pSer262/pSer356) are prominent in the characteristic globose neurofibrillary tangles and tufted astrocytes.[3:3] The predominance of 4R-tau isoforms in these disorders may render them particularly susceptible to MARK-mediated destabilization, as 4R-tau has an additional KXGS-containing repeat domain.[7]
MARK2 has been reported to phosphorylate alpha-synuclein at Ser129, the pathological phosphorylation site enriched in Lewy bodies, though this remains less established than its tau kinase activity.[8] MARK2 also regulates mitochondrial dynamics through phosphorylation of mitochondrial fission/fusion machinery components.
MARK kinases represent an attractive but challenging therapeutic target:
Drewes G, Ebneth A, Preuss U, et al. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell. 1997. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Timm T, Li XY, Biernat J, et al. MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1. EMBO J. 2003. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Chin JY, Bhatt LK, et al. MARK kinases in Alzheimer's disease and other tauopathies. Curr Alzheimer Res. 2010. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Marx A, Nugoor C, Panneerselvam S, Mandelkow E. Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases. FASEB J. 2010. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Chen YM, Bhatt LK, et al. Microtubule affinity-regulating kinase 2 functions downstream of the PAR-3/PAR-6/atypical PKC complex in regulating hippocampal neuronal polarity. Proc Natl Acad Sci USA. 2006. ↩︎ ↩︎ ↩︎
Nishimura I, Yang Y, Lu B. PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process leading to tau toxicity in Drosophila. Cell. 2004. ↩︎
Sergeant N, Bretteville A, Hamdane M, et al. Biochemistry of Tau in Alzheimer's disease and related neurological disorders. Expert Rev Proteomics. 2008. ↩︎
Lizcano JM, Goransson O, Toth R, et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004. ↩︎