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 overexpress ion of two MARK proteins from rat that arise from distinct genes. They encode Ser/Thr kinases of 88 and 81 kDa, respectively, and show simil arity to the yeast kin1(+) and C. elegans par-1 genes that are involve d in the establishment of cell polarity. Expression of both isoforms i s ubiquitous, and homologous genes are present in humans. Catalytic ac tivity depends on phosphorylation of two residues in subdomain VIII. O verexpression of MARK in cells leads to hyperphosphorylation of MAPs o n KXGS motifs and to disruption of the microtubule array, resulting in morphological changes and cell death.