Limits...
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.

Show MeSH

Related in: MedlinePlus

Recovery of anterograde transport of APP vesicles after coexpression of tau and MARK2. (a–c) RGC axon transfected with CFP-tau (a), YFP-MARK2 (b), and APP-mRFP (c). The time series in panel c shows recovery of anterograde movements. Open and closed arrowheads show two vesicles moving to the right at different speeds. (d) Histogram showing APP vesicle movements in control (left), after tau transfection (middle), after cotransfection of tau and MARK2 (right). In control cells almost all vesicles are mobile, and anterograde movements dominate. After tau transfection ∼40% of vesicles become immobile, and the net flow becomes retrograde. MARK2 partially relieves the inhibition by tau, the net flow becomes anterograde again.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2172520&req=5

fig8: Recovery of anterograde transport of APP vesicles after coexpression of tau and MARK2. (a–c) RGC axon transfected with CFP-tau (a), YFP-MARK2 (b), and APP-mRFP (c). The time series in panel c shows recovery of anterograde movements. Open and closed arrowheads show two vesicles moving to the right at different speeds. (d) Histogram showing APP vesicle movements in control (left), after tau transfection (middle), after cotransfection of tau and MARK2 (right). In control cells almost all vesicles are mobile, and anterograde movements dominate. After tau transfection ∼40% of vesicles become immobile, and the net flow becomes retrograde. MARK2 partially relieves the inhibition by tau, the net flow becomes anterograde again.

Mentions: Similar results on traffic inhibition were obtained with APP-vesicles (labeled with YFP) as a function of tau and MARK. In control RGCs, the majority of APP vesicles (80%) moved rapidly anterogradely with velocities up to 7 μm/s, a small fraction (∼20%) moved retrogradely, and only very few were in a pause state during the period of observation (20 min; Fig. 8). Expression of tau reversed the net flow of APP vesicles so that very few particles remained in the axons after 24 h (only ∼30% anterograde movements). However, coexpression of tau and MARK2 lead to a partial rescue of the traffic inhibition, the number of vesicles in the axons increased and the net flow became anterograde again (∼60% of particles). This reversal was not seen with the kinase-dead MARK2 mutant or with the KXGA-tau mutant.


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)

Recovery of anterograde transport of APP vesicles after coexpression of tau and MARK2. (a–c) RGC axon transfected with CFP-tau (a), YFP-MARK2 (b), and APP-mRFP (c). The time series in panel c shows recovery of anterograde movements. Open and closed arrowheads show two vesicles moving to the right at different speeds. (d) Histogram showing APP vesicle movements in control (left), after tau transfection (middle), after cotransfection of tau and MARK2 (right). In control cells almost all vesicles are mobile, and anterograde movements dominate. After tau transfection ∼40% of vesicles become immobile, and the net flow becomes retrograde. MARK2 partially relieves the inhibition by tau, the net flow becomes anterograde again.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: Recovery of anterograde transport of APP vesicles after coexpression of tau and MARK2. (a–c) RGC axon transfected with CFP-tau (a), YFP-MARK2 (b), and APP-mRFP (c). The time series in panel c shows recovery of anterograde movements. Open and closed arrowheads show two vesicles moving to the right at different speeds. (d) Histogram showing APP vesicle movements in control (left), after tau transfection (middle), after cotransfection of tau and MARK2 (right). In control cells almost all vesicles are mobile, and anterograde movements dominate. After tau transfection ∼40% of vesicles become immobile, and the net flow becomes retrograde. MARK2 partially relieves the inhibition by tau, the net flow becomes anterograde again.
Mentions: Similar results on traffic inhibition were obtained with APP-vesicles (labeled with YFP) as a function of tau and MARK. In control RGCs, the majority of APP vesicles (80%) moved rapidly anterogradely with velocities up to 7 μm/s, a small fraction (∼20%) moved retrogradely, and only very few were in a pause state during the period of observation (20 min; Fig. 8). Expression of tau reversed the net flow of APP vesicles so that very few particles remained in the axons after 24 h (only ∼30% anterograde movements). However, coexpression of tau and MARK2 lead to a partial rescue of the traffic inhibition, the number of vesicles in the axons increased and the net flow became anterograde again (∼60% of particles). This reversal was not seen with the kinase-dead MARK2 mutant or with the KXGA-tau mutant.

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