LATS1/WARTS phosphorylates MYPT1 to counteract PLK1 and regulate mammalian mitotic progression.
In the mitotic exit network of budding yeast, Dbf2 kinase phosphorylates and regulates Cdc14 phosphatase. In contrast, no phosphatase substrates of LATS1/WARTS kinase, the mammalian equivalent of Dbf2, has been reported. To address this discrepancy, we performed phosphoproteomic screening using LATS1 kinase. Screening identified MYPT1 (myosin phosphatase-targeting subunit 1) as a new substrate for LATS1. LATS1 directly and preferentially phosphorylated serine 445 (S445) of MYPT1. An MYPT1 mutant (S445A) failed to dephosphorylate Thr 210 of PLK1 (pololike kinase 1), thereby activating PLK1. This suggests that LATS1 promotes MYPT1 to antagonize PLK1 activity. Consistent with this, LATS1-depleted HeLa cells or fibroblasts from LATS1 knockout mice showed increased PLK1 activity. We also found deoxyribonucleic acid (DNA) damage-induced LATS1 activation caused PLK1 suppression via the phosphorylation of MYPT1 S445. Furthermore, LATS1 knockdown cells showed reduced G2 checkpoint arrest after DNA damage. These results indicate that LATS1 phosphorylates a phosphatase as does the yeast Dbf2 and demonstrate a novel role of LATS1 in controlling PLK1 at the G2 DNA damage checkpoint.
Division of Gene Regulation, Institute for Advanced Medical Research, Department of Obstetrics and Gynecology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Tatsuyuki
T
Chiyoda
Naoyuki
N
Sugiyama
Takatsune
T
Shimizu
Hideaki
H
Naoe
Yusuke
Y
Kobayashi
Jo
J
Ishizawa
Yoshimi
Y
Arima
Hiroshi
H
Tsuda
Masaaki
M
Ito
Kozo
K
Kaibuchi
Daisuke
D
Aoki
Yasushi
Y
Ishihama
Hideyuki
H
Saya
Shinji
S
Kuninaka
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D043263:Myosin-Light-Chain Phosphatase; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C092745:LATS1 protein, human; C490372:PPP1R12A protein, human