MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption.
MARK phosphorylates the microtubule-associated proteins tau, MAP2, and MAP4 on their microtubule-binding domain, causing their dissociation from microtubules and increased microtubule dynamics. We describe the molecular cloning, distribution, activation mechanism, and overexpression of two MARK proteins from rat that arise from distinct genes. They encode Ser/Thr kinases of 88 and 81 kDa, respectively, and show similarity to the yeast kin1+ and C. elegans par-1 genes that are involved in the establishment of cell polarity. Expression of both isoforms is ubiquitous, and homologous genes are present in humans. Catalytic activity depends on phosphorylation of two residues in subdomain VIII. Overexpression of MARK in cells leads to hyperphosphorylation of MAPs on KXGS motifs and to disruption of the microtubule array, resulting in morphological changes and cell death.
Drewes
G
G
Max-Planck-Unit for Structural Molecular Biology, Hamburg, Germany.
Ebneth
A
A
Preuss
U
U
Mandelkow
E M
EM
Mandelkow
E
E
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009928:Organ Specificity; D010446:Peptide Fragments / Q000235:genetics; D010766:Phosphorylation; D010802:Phylogeny; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D013552:Swine; D016875:tau Proteins / Q000378:metabolism
D018076:DNA, Complementary; D010446:Peptide Fragments; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D016875:tau Proteins; C105547:MARK1 protein, human; C105549:MARK2 protein, rat; C484552:Mark1 protein, rat; D017346:Protein Serine-Threonine Kinases