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

  title={MARK, a Novel Family of Protein Kinases That Phosphorylate Microtubule-Associated Proteins and Trigger Microtubule Disruption},
  author={Gerard Drewes and Andreas Ebneth and Ute Preuss and Eva-Maria Mandelkow and Eckhard Mandelkow},

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MARK4 Is a Novel Microtubule-associated Proteins/Microtubule Affinity-regulating Kinase That Binds to the Cellular Microtubule Network and to Centrosomes*

It is suggested that although the four MARK/PAR-1 kinases might play multiple cellular roles in concert with different targets, MARK4 is likely to be directly involved in microtubule organization in neuronal cells and may contribute to the pathological phosphorylation of tau in Alzheimer's disease.

Microtubule Affinity-Regulating Kinase 4: Structure, Function, and Regulation

MAP/Microtubule affinity-regulating kinase 4 (MARK4) belongs to the family of serine/threonine kinases that phosphorylate the microtubule-associated proteins (MAP) causing their detachment from the

Phosphorylation of MAP2c and MAP4 by MARK kinases leads to the destabilization of microtubules in cells.

It is shown that MAP/microtubule affinity regulating kinases (MARK) can phosphorylate the microtubule-associated-proteins MAP4, MAP2c, and tau on their microtubULE-binding domain in vitro, leading to their detachment from microtubules (MT) and an increased dynamic instability of MT.

MAPs, MARKs and microtubule dynamics.

Atypical PKC phosphorylates microtubule affinity-regulating kinase 4 in vitro

A functional link between atypical protein kinase c (aPKC) and MARK4, two central determinants of cell polarity, is confirmed and it suggests that aPKC may regulate all four members of Par-1 through phosphorylating them in polarized cells.

Structural variations in catalytic and ubiquitin –associated domains of Human protein kinase MARK1 and MARK3

Kinase assays showed that, MARK1 and 2 kinases are activated to a greater extent on deleting the UBA domain than on retaining it, and these results are consistent with the crystal structures of MARK, with regard to the binding of the U BA domain and its role in enforcing an open, inactive conformation of the MARK kinases.

Identification of potent inhibitors of microtubule affinity regulating kinase for inhibition of tau hyperphosphorylation

The aim was to identify a potent and selective ATP-competitive MARK inhibitor that could be used for ‘proof of concept’ studies in transgenic mice expressing human tau and potentially as a starting point for a drug development program.

Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity.

The results suggest that MARK2 contributes to the plasticity of microtubules needed for neuronal polarity and the growth of neurites.

Crystal structure of the catalytic and ubiquitin-associated domains of the protein kinase MARK2 / PAR-1 from Rattus norvegicus (Berkenhout, 1769)

The ubiquitin-binding interface is partially masked by the interaction with the kinase domain, implying that detachment and/or conformational changes are necessary for activation of ubiquit in-dependent signaling.



Phosphorylation of Microtubule-associated Proteins MAP2 and MAP4 by the Protein Kinase p110

It is shown that p110 phosphorylates analogous KXGS sites in the microtubule binding domains of the neuronal MAP2 and the ubiquitous MAP4, which leads to the dissociation ofMAP2 and MAP4 from microtubules and to a pronounced increase in dynamic instability.

A Microtubule-associated Protein (MAP2) Kinase Restores Microtubule Motility in Embryonic Brain (*)

In vivo, embryonic MAP2 kinase could play a major role in the regulation of motility and positioning of membranous organelles within the cells even at substoichiometric levels.

Phosphorylation of microtubule‐associated protein tau: identification of the site for Ca2(+)‐calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles.

It is shown that a single phosphorylation site is responsible for the pronounced shift in electrophoretic mobility characteristic for tau from Alzheimer neurofibrillary tangles, located at Ser 405 in the C‐terminal tail of the protein outside the region of internal repeats.

Domains of tau protein, differential phosphorylation, and dynamic instability of microtubules.

The effect of the neuronal microtubule-associated protein tau is described by observing the dynamics of single microtubules by video microscopy and confirming the presence of a "hotspot" of binding potential involving Lys274 and Lys281 observed by Goode and Feinstein, 1994.

Microtubule-associated Protein/Microtubule Affinity-regulating Kinase (p110mark)

The purification and characterization of a protein-serine kinase from brain tissue with an apparent molecular mass of 110 kDa on SDS gels are described and a role for this novel kinase in cellular events involving rearrangement of the microtubule-associated proteins/microtubule arrays and their pathological degeneration in Alzheimer's disease is suggested.

Structure and phosphorylation of microtubule-associated protein 2 (MAP 2).

  • R. Vallee
  • Chemistry, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1980
Both the assembly-promoting fragments and fragments representing the portion of the MAP 2 molecule observed as a projection on the microtubule surface were found to contain sites for endogenous cyclic AMP-dependent phosphorylation and an intimate association of a kinase activity with the projections.

Regulation of a major microtubule‐associated protein by MPF and MAP kinase.

The results suggest that the drastic change in p220 activity during the transition from interphase to M phase may be induced by its phosphorylation in M phase probably catalyzed by MAP kinase and MPF.