MARK, a Novel Family of Protein Kinases That Phosphorylate Microtubule-Associated Proteins and Trigger Microtubule Disruption

Drewes, Gerard; Ebneth, Andreas; Preuss, Ute; Mandelkow, Eva-Maria; Mandelkow, Eckhard

doi:10.1016/s0092-8674(00)80208-1

Cited by 878Microtubule and mitosis dynamicsProtein Kinase Regulation and GTPase SignalingNeurogenesis and neuroplasticity mechanisms

MARK, a Novel Family of Protein Kinases That Phosphorylate Microtubule-Associated Proteins and Trigger Microtubule Disruption

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Drewes, Gerard, Ebneth, Andreas, Preuss, Ute, Mandelkow, Eva-Maria, Mandelkow, Eckhard·1997·Cell

DOI 10.1016/s0092-8674(00)80208-1

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Abstract

MARK phosphorylates the microtubule-associated proteins tau, MAP2, and MAP4 on their microtubule-binding domain, causing their dissociation from microtubules and increased microtubule dynamics. We describe the molecular cloning, distribution, activation mechanism, and overexpression of two MARK proteins from rat that arise from distinct genes. They encode Ser/Thr kinases of 88 and 81 kDa, respectively, and show similarity to the yeast kin1+ and C. elegans par-1 genes that are involved in the establishment of cell polarity. Expression of both isoforms is ubiquitous, and homologous genes are present in humans. Catalytic activity depends on phosphorylation of two residues in subdomain VIII. Overexpression of MARK in cells leads to hyperphosphorylation of MAPs on KXGS motifs and to disruption of the microtubule array, resulting in morphological changes and cell death.

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PAR-1/MARK-2 phosphorylates tau at the S262/S356 sites, causing a significant reduction in binding affinity of tau for microtubules.
“PAR-1/MARK-2 (mammalian homolog microtubule-associated protein/microtubule affinity-regulating kinase 2) has been shown to phosphorylate tau at the S262/S356 sites, causing a significant reduction in binding affinity of tau for microtubules (26).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [26]
Tau phosphorylation at Ser262/356 decreases tau's affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice.
“Tau phosphorylation at these sites decreases the protein’s affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice [18, 19, 25–27, 50–52].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [50]
PAR-1/MARKs are non-SP/TP kinases that phosphorylate tau at Ser262 and Ser356 in the repeat domains located in the microtubule-binding region.
“whereas PAR-1/MARKs are non-SP/TP kinases that phosphorylate tau at Ser262 and Ser356 in the repeat domains located in the microtubule-binding region [50].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [50]
Phosphorylation at Ser262 and Ser356 decreases tau binding to microtubules.
“Ser262 and Ser356 are located in the microtubule-binding domain, and phosphorylation at these sites decreases tau binding to microtubules [18, 19, 25, 26, 50, 51].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [50]

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Authors: Drewes, G., Ebneth, A., Preuss, U., Mandelkow, E.-M., & Mandelkow, E.
Affiliations: Max Planck Unit for Structural Molecular Biology (DE)
Corresponding author: Drewes, Gerard
ORCID: Drewes, Gerard
Mandelkow, Eva-Maria
Venue: Cell
Publisher: Elsevier BV
Published: 1997-04
Volume: 89
Issue: 2
Pages: 297-308
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/s0092-8674(00)80208-1
OpenAlex: W2001443225
Cited by: 878
References: 2
Citations by year: 2026: 15 · 2025: 22 · 2024: 33 · 2023: 29 · 2022: 26 · 2021: 21 · 2020: 29 · 2019: 29 · 2018: 21 · 2017: 38 · 2016: 31 · 2015: 25 · 2014: 23 · 2013: 38 · 2012: 32
FWCI: 12.74
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 5951 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Desy publication database (The Deutsches Elektronen-Synchrotron) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords: Mark, protein kinases, microtubule-associated proteins, tau protein, MAP2, MAP4, microtubule dynamics, microtubule disruption, cell polarity, KIN1, protease-activated receptor 1, kinase activation, cell death
MeSH terms: Amino Acid Sequence, Animals, Cloning, Molecular, Cricetinae, Humans, Microtubules, Molecular Sequence Data, Molecular Weight, Organ Specificity, Peptide Fragments, Phosphorylation, Phylogeny, Recombinant Fusion Proteins, RNA, Messenger, Substrate Specificity, Swine, Gene Expression, CHO Cells, tau Proteins, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Sequence Analysis, DNA, DNA, Complementary, Rats

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MARK, a Novel Family of Protein Kinases That Phosphorylate Microtubule-Associated Proteins and Trigger Microtubule Disruption

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