MARK2 is a serine/threonine kinase that phosphorylates microtubule-associated proteins (MAPs) including [tau](/proteins/tau), regulating microtubule dynamics and neuronal polarity. Dysregulation of MARK2 activity contributes to tau hyperphosphorylation in [Alzheimer's disease](/diseases/alzheimers-disease) and other [tauopathies](/mechanisms/tauopathies). [@ando2013]
MARK2 is a serine/threonine kinase that phosphorylates microtubule-associated proteins (MAPs) including [tau](/proteins/tau), regulating microtubule dynamics and neuronal polarity. Dysregulation of MARK2 activity contributes to tau hyperphosphorylation in [Alzheimer's disease](/diseases/alzheimers-disease) and other [tauopathies](/mechanisms/tauopathies). [@ando2013]
<div class="infobox infobox-gene"> [@timm2003]
| Property | Value | [@hurov2001] |----------|-------| [@sun2016] | Gene Symbol | MARK2 | [@lund2014] | Full Name | MAP/Microtubule Affinity-Regulating Kinase 2 | | Aliases | EMK1, Par-1b, ELKL motif kinase 1 | | Chromosomal Location | 11q12.2 | | NCBI Gene ID | [2011](https://www.ncbi.nlm.nih.gov/gene/2011) | | OMIM ID | [600526](https://omim.org/entry/600526) | | Ensembl ID | [ENSG00000072518](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000072518) | | UniProt ID | [Q7KZI7](https://www.uniprot.org/uniprot/Q7KZI7) | | Encoded Protein | [MARK2 Protein](/proteins/mark2-protein) | | Associated Diseases | Alzheimer's disease, tauopathies, autism spectrum disorder |
</div>
Introduction
MARK2 (MAP/Microtubule Affinity-Regulating Kinase 2), also known as Par-1b or EMK1, is a member of the AMPK-related kinase family. It was originally identified as a partitioning-defective (Par) gene product in C. elegans, where it is essential for asymmetric cell division and polarity establishment. In mammals, MARK2 plays critical roles in neuronal polarity, axon specification, microtubule dynamics, and intracellular transport. It is one of the primary kinases responsible for phosphorylating tau at the KXGS motifs (Ser262 and Ser356) within the microtubule-binding repeats, a modification that profoundly reduces tau's affinity for microtubules and is observed early in Alzheimer's disease pathogenesis.
Function
Tau Phosphorylation and Microtubule Regulation
MARK2 is one of four MARK family kinases ([MARK1](/genes/mark1), MARK2, [MARK3](/genes/mark3), [MARK4](/genes/mark4)) that phosphorylate tau at KXGS motifs within microtubule-binding repeats:
Ser262 phosphorylation — The primary MARK2 target on tau; phosphorylation at this site alone reduces tau-microtubule binding by ~10-fold
Ser356 phosphorylation — Second major target; combined Ser262/Ser356 phosphorylation virtually abolishes tau-microtubule interaction
MARK2 is tightly regulated by multiple mechanisms:
LKB1 activation — The master kinase [LKB1/STK11](/genes/stk11) phosphorylates MARK2 at Thr208 in the activation loop, the primary activating event
aPKC inhibition — Atypical protein kinase C phosphorylates MARK2 at Thr595, targeting it for degradation and establishing polarity asymmetry
GSK3β priming — [GSK3β](/genes/gsk3b) can prime MARK2 substrates, creating cooperative phosphorylation cascades on tau
MARKK/TAO1 activation — Thousand-and-one kinase (TAO1) also activates MARK2 by activation loop phosphorylation
14-3-3 binding — Phosphorylated MARK2 binds 14-3-3 proteins, which sequester it in the cytoplasm
Disease Associations
Alzheimer's Disease
MARK2 is strongly implicated in AD pathogenesis through multiple mechanisms:
Early tau pathology — Phosphorylation of tau at Ser262 (a MARK site) is one of the earliest pathological tau modifications, preceding PHF formation and NFT accumulation
[Amyloid-beta](/proteins/amyloid-beta) activation — Aβ oligomers activate MARK2 through disruption of the LKB1-MARK signaling axis, creating a feed-forward loop between amyloid and tau pathology
Synaptic toxicity — MARK2-dependent tau phosphorylation in [dendritic spines](/mechanisms/dendritic-spines) contributes to postsynaptic dysfunction and spine loss in AD
Axonal transport deficits — Excessive MARK2 activity strips tau from microtubules, disrupting axonal transport of mitochondria, vesicles, and signaling endosomes
Kinase cascade interaction — MARK2 cooperates with [CDK5](/genes/cdk5) and [GSK3β](/genes/gsk3b) in sequential tau phosphorylation, each kinase priming sites for the others
Frontotemporal Dementia (FTD)
[MAPT](/proteins/tau) mutations — Several FTD-causing [MAPT](/genes/mapt) mutations (e.g., P301L, V337M) alter tau's susceptibility to MARK2 phosphorylation
Increased MARK activity — FTLD-Tau brain tissue shows elevated MARK family kinase activity
Autism Spectrum Disorder
De novo mutations — Rare de novo MARK2 variants have been identified in individuals with autism spectrum disorder
Neuronal migration — MARK2 regulates neuronal migration during cortical development; disruption may contribute to neurodevelopmental phenotypes
Other Associations
Parkinson's disease — MARK2 phosphorylation of tau may contribute to tau co-pathology observed in [PD](/diseases/parkinsons-disease)
Traumatic brain injury — MARK activity is elevated following TBI, potentially linking acute injury to chronic tauopathy
Expression
MARK2 shows broad but enriched neural expression:
Brain regions — Highly expressed in [hippocampus](/brain-regions/hippocampus) (CA1, CA3, dentate gyrus), cerebral [cortex](/brain-regions/cortex) (layers II-VI), cerebellum (Purkinje cells), and basal ganglia
Cell types — Predominantly neuronal; also expressed in [astrocytes](/cell-types/astrocytes) and [oligodendrocytes](/cell-types/oligodendrocytes)
[Drewes et al., MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption (1997) (1997)](https://doi.org/10.1016/S0092-8674(00)
[Unknown, Matenia & Mandelkow, The tau of MARK: a polarized view of the cytoskeleton (2009) (2009)](https://doi.org/10.1016/j.tibs.2009.03.008)
[Nishimura et al., PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process leading to tau inclusion in Alzheimer's disease (2004) (2004)](https://doi.org/10.1016/j.cell.2004.11.038)
[Ando et al., Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker (2013) (2013)](https://doi.org/10.1016/j.neurobiolaging.2012.10.015)
[Timm et al., MARKK, a Ste20-like kinase, activates the polarity kinase MARK/PAR-1 (2003) (2003)](https://doi.org/10.1093/emboj/cdg583)
[Hurov et al., Immune system dysfunction and autoimmune disease in mice lacking Emk (Par-1) protein kinase (2001) (2001)](https://doi.org/10.1128/MCB.21.9.3206-3219.2001)
[Sun et al., The role of MARK2/Par-1 in neuronal polarity and tau phosphorylation (2016) (2016)](https://doi.org/10.1016/j.neuroscience.2016.01.018)
[Lund et al., Phosphorylation of tau at Ser262 in Alzheimer's disease brain is an early event (2014) (2014)](https://doi.org/10.1016/j.neurobiolaging.2013.09.027)