MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons.
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.
Mandelkow
Eva-Maria
EM
Max-Planck Unit for Structural Molecular Biology, 22607 Hamburg, Germany. mandelkow@mpasmb.desy.de
Thies
Edda
E
Trinczek
Bernhard
B
Biernat
Jacek
J
Mandelkow
Eckard
E
D000256:Adenoviridae / Q000235:genetics; D020816:Amino Acid Motifs; D000818:Animals; D001369:Axons / Q000378:metabolism*; D001692:Biological Transport; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism
D016875:tau Proteins; C105547:MARK1 protein, human; D017346:Protein Serine-Threonine Kinases