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MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons.

Mandelkow EM, Thies E, Trinczek B, Biernat J, Mandelkow E - J. Cell Biol. (2004)

Bottom Line: The transport can be regulated through motor proteins, cargo adaptors, or microtubule tracks.This occurs without impairing the intrinsic activity of motors because the velocity during active movement remains unchanged.This transport inhibition can be rescued by phosphorylating tau with MARK.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck Unit for Structural Molecular Biology, 22607 Hamburg, Germany. mandelkow@mpasmb.desy.de

ABSTRACT
Microtubule-dependent transport of vesicles and organelles appears saltatory because particles switch between periods of rest, random Brownian motion, and active transport. The transport can be regulated through motor proteins, cargo adaptors, or microtubule tracks. We report here a mechanism whereby microtubule associated proteins (MAPs) represent obstacles to motors which can be regulated by microtubule affinity regulating kinase (MARK)/Par-1, a family of kinases that is known for its involvement in establishing cell polarity and in phosphorylating tau protein during Alzheimer neurodegeneration. Expression of MARK causes the phosphorylation of MAPs at their KXGS motifs, thereby detaching MAPs from the microtubules and thus facilitating the transport of particles. This occurs without impairing the intrinsic activity of motors because the velocity during active movement remains unchanged. In primary retinal ganglion cells, transfection with tau leads to the inhibition of axonal transport of mitochondria, APP vesicles, and other cell components which leads to starvation of axons and vulnerability against stress. This transport inhibition can be rescued by phosphorylating tau with MARK.

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Model of MAPs and MARK regulating the movement of motors along microtubules. (Top) Unphosphorylated MAPs are attached to microtubules and present obstacles to motors such as kinesin (short run length, inhibition of attachment of motors). (Bottom) MAPs phosphorylated by MARK detach from microtubules and thus clear the path for motors.
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fig9: Model of MAPs and MARK regulating the movement of motors along microtubules. (Top) Unphosphorylated MAPs are attached to microtubules and present obstacles to motors such as kinesin (short run length, inhibition of attachment of motors). (Bottom) MAPs phosphorylated by MARK detach from microtubules and thus clear the path for motors.

Mentions: The results summarized in Fig. 9 show that the cell is capable of enhancing the motility of vesicles and organelles by activating the kinase MARK2. This kinase mainly targets the KXGS motifs in MAP4, MAP2, and tau, thereby removing them from the microtubule surface. Conversely, overexpression of MAPs overwhelms the kinase and leads to clogging of tracks and traffic inhibition, independently of the stabilization of microtubules. It is possible that this kinase also explains the phosphorylation-induced enhancement of vesicle motility observed by other authors (Lopez and Sheetz, 1995; Sato-Harada et al., 1996). The mechanism appears to be similar with all cargoes and MAPs studied so far (demonstrated here for the case of VSV-G vesicles, clathrin-coated vesicles, APP-vesicles, lysosomes, and mitochondria; Figs. 4, 6, and 8). It is based on an apparent extension of the run length without change in the instantaneous velocities. This means that the motor activity itself is not affected, but the probability of motor attachment is increased because there are fewer MAPs as obstacles in their way.


MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons.

Mandelkow EM, Thies E, Trinczek B, Biernat J, Mandelkow E - J. Cell Biol. (2004)

Model of MAPs and MARK regulating the movement of motors along microtubules. (Top) Unphosphorylated MAPs are attached to microtubules and present obstacles to motors such as kinesin (short run length, inhibition of attachment of motors). (Bottom) MAPs phosphorylated by MARK detach from microtubules and thus clear the path for motors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172520&req=5

fig9: Model of MAPs and MARK regulating the movement of motors along microtubules. (Top) Unphosphorylated MAPs are attached to microtubules and present obstacles to motors such as kinesin (short run length, inhibition of attachment of motors). (Bottom) MAPs phosphorylated by MARK detach from microtubules and thus clear the path for motors.
Mentions: The results summarized in Fig. 9 show that the cell is capable of enhancing the motility of vesicles and organelles by activating the kinase MARK2. This kinase mainly targets the KXGS motifs in MAP4, MAP2, and tau, thereby removing them from the microtubule surface. Conversely, overexpression of MAPs overwhelms the kinase and leads to clogging of tracks and traffic inhibition, independently of the stabilization of microtubules. It is possible that this kinase also explains the phosphorylation-induced enhancement of vesicle motility observed by other authors (Lopez and Sheetz, 1995; Sato-Harada et al., 1996). The mechanism appears to be similar with all cargoes and MAPs studied so far (demonstrated here for the case of VSV-G vesicles, clathrin-coated vesicles, APP-vesicles, lysosomes, and mitochondria; Figs. 4, 6, and 8). It is based on an apparent extension of the run length without change in the instantaneous velocities. This means that the motor activity itself is not affected, but the probability of motor attachment is increased because there are fewer MAPs as obstacles in their way.

Bottom Line: The transport can be regulated through motor proteins, cargo adaptors, or microtubule tracks.This occurs without impairing the intrinsic activity of motors because the velocity during active movement remains unchanged.This transport inhibition can be rescued by phosphorylating tau with MARK.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck Unit for Structural Molecular Biology, 22607 Hamburg, Germany. mandelkow@mpasmb.desy.de

ABSTRACT
Microtubule-dependent transport of vesicles and organelles appears saltatory because particles switch between periods of rest, random Brownian motion, and active transport. The transport can be regulated through motor proteins, cargo adaptors, or microtubule tracks. We report here a mechanism whereby microtubule associated proteins (MAPs) represent obstacles to motors which can be regulated by microtubule affinity regulating kinase (MARK)/Par-1, a family of kinases that is known for its involvement in establishing cell polarity and in phosphorylating tau protein during Alzheimer neurodegeneration. Expression of MARK causes the phosphorylation of MAPs at their KXGS motifs, thereby detaching MAPs from the microtubules and thus facilitating the transport of particles. This occurs without impairing the intrinsic activity of motors because the velocity during active movement remains unchanged. In primary retinal ganglion cells, transfection with tau leads to the inhibition of axonal transport of mitochondria, APP vesicles, and other cell components which leads to starvation of axons and vulnerability against stress. This transport inhibition can be rescued by phosphorylating tau with MARK.

Show MeSH
Related in: MedlinePlus