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      Ndr protein kinase is regulated by phosphorylation on two conserved sequence motifs.

      The Journal of Biological Chemistry
      3-Phosphoinositide-Dependent Protein Kinases, Amino Acid Sequence, Animals, Binding Sites, COS Cells, Cell Line, Transformed, Conserved Sequence, Humans, Mass Spectrometry, methods, Molecular Sequence Data, Nuclear Proteins, genetics, metabolism, Phosphorylation, Protein-Serine-Threonine Kinases, Sequence Analysis, Sequence Homology, Amino Acid, Serine, Threonine

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          Abstract

          Ndr is a nuclear serine/threonine protein kinase that belongs to a subfamily of kinases implicated in the regulation of cell division and cell morphology. This subfamily includes the kinases LATS, Orb6, Cot-1, and Dbf2. We show here that Ndr is potently activated when intact cells are treated with okadaic acid, suggesting that Ndr is normally held in a state of low activity by protein phosphatase 2A. We mapped the regulatory phosphorylation sites of Ndr protein kinase and found that active Ndr is phosphorylated on Ser-281 and Thr-444. Mutation of either site to alanine strongly reduced both basal and okadaic acid-stimulated Ndr activity, while combined mutation abolished Ndr activity completely. Importantly, each of these sites (and also the surrounding sequences) are conserved in the kinase relatives of Ndr, suggesting a general mechanism of activation for kinases of this subfamily. Ser-281 and Thr-444 are also similar to the regulatory phosphorylation sites in several targets of the phosphoinositide-dependent protein kinase PDK1.(1) However, PDK1 does not appear to function as an upstream kinase for Ndr. Thus, Ndr and its close relatives may operate in a novel signaling pathway downstream of an as-yet-unidentified kinase with specificity similar to, but distinct from, PDK1.

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