Phospho-regulation of KIBRA by CDK1 and CDC14 phosphatase controls cell-cycle progression.
KIBRA (kidney- and brain-expressed protein) is a novel regulator of the Hippo pathway, which controls tissue growth and tumorigenesis by regulating both cell proliferation and apoptosis. In mammals, KIBRA is associated with memory performance. The physiological function and regulation of KIBRA in non-neuronal cells remain largely unclear. We reported recently that KIBRA is phosphorylated by the mitotic kinases Aurora-A and -B. In the present study, we have expanded our analysis of KIBRA's role in cell-cycle progression. We show that KIBRA is also phosphorylated by CDK1 (cyclin-dependent kinase 1) in response to spindle damage stress. We have identified KIBRA Ser(542) and Ser(931) as main phosphorylation sites for CDK1 both in vitro and in vivo. Moreover, we found that the CDC (cell division cycle) 14A/B phosphatases associate with KIBRA, and CDK1-non-phosphorylatable KIBRA has greatly reduced interaction with CDC14B. CDC14A/B dephosphorylate CDK1-phosphorylated KIBRA in vitro and in cells. By using inducible-expression cell lines, we show further that phospho-regulation of KIBRA by CDK1 and CDC14 is involved in mitotic exit under spindle stress. Our results reveal a new mechanism through which KIBRA regulates cell-cycle progression.
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Ming
M
Ji
Shuping
S
Yang
Yuanhong
Y
Chen
Ling
L
Xiao
Lin
L
Zhang
Jixin
J
Dong
D000595:Amino Acid Sequence; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D017239:Paclitaxel / Q000494:pharmacology; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases; D011687:Purines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000077546:Roscovitine
D019926:Cyclin B; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011687:Purines; D011993:Recombinant Fusion Proteins; C513637:WWC1 protein, human; D000077546:Roscovitine; D016203:CDC2 Protein Kinase; D010744:Phosphoric Monoester Hydrolases; C120902:CDC14A protein, human; C474200:CDC14B protein, human; D054637:Dual-Specificity Phosphatases; D017027:Protein Tyrosine Phosphatases; D017239:Paclitaxel