title: PLK1-dependent activation of LRRK1 regulates spindle orientation by phosphorylating CDK5RAP2.
abstract: Correct formation of the cell division axis requires the initial precise orientation of the mitotic spindle. Proper spindle orientation depends on centrosome maturation, and Polo-like kinase 1 (PLK1) is known to play a crucial role in this process. However, the molecular mechanisms that function downstream of PLK1 are not well understood. Here we show that LRRK1 is a PLK1 substrate that is phosphorylated on Ser 1790. PLK1 phosphorylation is required for CDK1-mediated activation of LRRK1 at the centrosomes, and this in turn regulates mitotic spindle orientation by nucleating the growth of astral microtubules from the centrosomes. Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its γ-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with γ-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation. Thus, our findings provide evidence that LRRK1 regulates mitotic spindle orientation downstream of PLK1 through CDK5RAP2-dependent centrosome maturation.
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hanafusa
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Kedashiro
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tezuka
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Funatsu
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Usami
authors.affiliation: Department of Cell Biology, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Toyoshima
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D016203:CDC2 Protein Kinase; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D018385:Centrosome / Q000201:enzymology; D002522:Chlorocebus aethiops; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000201:enzymology; D008938:Mitosis; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012694:Serine; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000201:enzymology*; D013997:Time Factors; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D018844:Cyclin-Dependent Kinases; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012694:Serine; D014404:Tubulin; D000097869:Polo-Like Kinase 1; C405929:CDK5RAP2 protein, human; C510751:LRRK1 protein, human; C528899:CDK1 protein, human