PAK5 kinase is an inhibitor of MARK/Par-1, which leads to stable microtubules and dynamic actin.
MARK/Par-1 is a kinase involved in development of embryonic polarity. In neurons, MARK phosphorylates tau protein and causes its detachment from microtubules, the tracks of axonal transport. Because the target sites of MARK on tau occur at an early stage of Alzheimer neurodegeneration, we searched for interaction partners of MARK. Here we report that MARK2 is negatively regulated by PAK5, a neuronal member of the p21-activated kinase family. PAK5 suppresses the activity of MARK2 toward its target, tau protein. The inhibition requires the binding between the PAK5 and MARK2 catalytic domains, but does not require phosphorylation. In transfected Chinese hamster ovary (CHO) cells both kinases show a vesicular distribution with partial colocalization on endosomes containing AP-1/2. Although MARK2 transfected alone destabilizes microtubules and stabilizes actin stress fibers, PAK5 keeps microtubules stable through the down-regulation of MARK2 but destabilizes the F-actin network so that stress fibers and focal adhesions disappear and cells develop filopodia. The results point to an inverse relationship between actin- and microtubule-related signaling by the PAK5 and MARK2 pathways that affect both cytoskeletal networks.
Matenia
Dorthe
D
Max-Planck-Unit for Structural Molecular Biology, 22607 Hamburg, Germany.
Griesshaber
Bettina
B
Li
Xiao-yu
XY
Thiessen
Anja
A
Johne
Cindy
C
Jiao
Jian
J
Mandelkow
Eckhard
E
Mandelkow
Eva-Maria
EM
D000199:Actins / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D020134:Catalytic Domain; D006224:Cricetinae; D022162:Cytoplasmic Vesicles / Q000201:enzymology / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D008870:Microtubules / Q000201:enzymology / Q000378:metabolism*; D025941:Protein Interaction Mapping / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D044463:Receptor, PAR-1 / Q000378:metabolism / Q000502:physiology; D014162:Transfection; D054462:p21-Activated Kinases; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors
D000199:Actins; D044463:Receptor, PAR-1; D016875:tau Proteins; C094670:MARK2 protein, human; C443802:PAK5 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D010975:Platelet Aggregation Inhibitors