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Pten regulates spindle pole movement through Dlg1-mediated recruitment of Eg5 to centrosomes

Nature Cell Biology volume 18, pages 814–821 (2016)Cite this article

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Abstract

Phosphatase and tensin homologue (Pten) suppresses neoplastic growth by negatively regulating PI(3)K signalling through its phosphatase activity1. To gain insight into the actions of non-catalytic Pten domains in normal physiological processes and tumorigenesis2,3, we engineered mice lacking the PDZ-binding domain (PDZ-BD). Here, we show that the PDZ-BD regulates centrosome movement and that its heterozygous or homozygous deletion promotes aneuploidy and tumour formation. We found that Pten is recruited to pre-mitotic centrosomes in a Plk1-dependent fashion to create a docking site for protein complexes containing the PDZ-domain-containing protein Dlg1 (also known as Sap97) and Eg5 (also known as Kif11), a kinesin essential for centrosome movement and bipolar spindle formation4. Docking of Dlg1–Eg5 complexes to Pten depended on Eg5 phosphorylation by the Nek9–Nek6 mitotic kinase cascade and Cdk1. PDZ-BD deletion or Dlg1 ablation impaired loading of Eg5 onto centrosomes and spindle pole motility, yielding asymmetrical spindles that are prone to chromosome missegregation. Collectively, these data demonstrate that Pten, through the Dlg1-binding ability of its PDZ-BD, accumulates phosphorylated Eg5 at duplicated centrosomes to establish symmetrical bipolar spindles that properly segregate chromosomes, and suggest that this function contributes to tumour suppression.

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Figure 1: The PDZ-BD of Pten is required for proper chromosome segregation.
Figure 2: Pten interacts with the PDZ-domain-containing protein Dlg1 to regulate centrosome movement during mitotic spindle assembly.
Figure 3: Pten at centrosomes creates a docking site for Eg5-bound Dlg1.
Figure 4: PTEN accumulates at centrosomes following phosphorylation by PLK1 to load DLG1-bound EG5 modified by NEK9–NEK6 kinases.
Figure 5: The Pten PDZ-BD acts to suppress tumorigenesis.

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Acknowledgements

We thank W. Zhou and M. Li of Mayo Clinic’s Gene Knockout Mouse Core Facility for embyronic stem cell microinjection and chimaera breeding, and A. Alimonti, P. Galardy, D. Baker, R. Naylor and members of the van Deursen laboratory for critical reading of the manuscript and for providing helpful comments and discussion. We are grateful to J. Roig for providing various critical reagents. This work was supported by the National Institutes of Health (CA168709 to J.M.v.D.).

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Authors and Affiliations

  1. Departments of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

    Janine H. van Ree, Hyun-Ja Nam, Karthik B. Jeganathan, Arun Kanakkanthara & Jan M. van Deursen

  2. Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA

    Jan M. van Deursen

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Contributions

J.M.v.D. and J.H.v.R. conceived the project. J.H.v.R., H.-J.N. and K.B.J. performed the experimental work. A.K. performed DNA replication and damage analyses. All authors analysed the data and prepared figures. J.M.v.D., J.H.v.R. and H.-J.N. wrote the manuscript and all authors edited the manuscript. J.M.v.D. supervised all aspects of the project.

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Correspondence to Jan M. van Deursen.

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Integrated supplementary information

Supplementary Figure 1 Akt signaling and structural chromosome integrity seems unaffected by PDZ-BD loss.

(a) Analysis of metaphase spreads from P5 MEFs for abnormal chromosome numbers and DSBs. n = the number of independent MEF lines (50 and 100 spreads per line were analyzed for assessments of aneuploidy and chromosome breaks, respectively). (b) Growth curves of induced and non-induced MEFs containing the indicated Pten expression constructs. n = 3 independent MEF lines for each growth curve. Note that induction of ectopic expression of WT or mutant PTEN proteins had no negative impact on cell proliferation. (c) Western blots of lysates from WT MEFs carrying HA-tagged AKTMyr introduced by a lentiviral expression vector (EV, empty vector). (d) Western blots of lysates from WT and PtenΔTKV /ΔTKV MEFs, spleens and livers. Pon S staining of blotted proteins served as a loading control. (e) Western blot of asynchronous MEF extracts. Pon S staining served as a loading control. (f) Incidence of MEFs with ≥2γ-H2AX/53BP1-positive foci. n = 3 independent MEF lines (n = 500 cells per line). (g) EGFP-PTEN localization in MEFs before and 4 h after 5 Gy γ-irradiation.γ-H2AX (in red) co-staining was used as a marker for DNA damage. Bar, 5 μm. (h) Quantitation of MEFs with nuclear EGFP-PTEN localization before and 4 h after γ- irradiation. n = 3 independent MEF lines. (i, j) Analysis of DSB repair following 5 Gy γ-irradiation using γ-H2AX and 53BP1 as DSB markers. Quantification was done on n = 3 independent MEF lines (119–191 cells per line). (k) Analysis of DNA replication efficiency using DNA fiber assays. This analysis was carried out on n = 3 independent MEF lines (102–202 replication forks per line). Data in b and h–k represent mean ± s.e.m., and in a and f mean ± s.d. Statistical significance was determined by a two-tailed unpaired t-test. ∗∗∗, P < 0.001. Unprocessed original scans of blots can be found in Supplementary Fig. 6 and Statistics Source Data in Supplementary Table 1.

Supplementary Figure 2 Mitotic surveillance mechanisms are not affected in PtenΔTKV /ΔTKV MEFs.

(a) WT MEFs with or without knockdown of Par3 or Nherf1 monitored for mitotic defects by live-cell imaging as they progress through mitosis. n = the number of independent experiments (≥24 cells per line). (b) Spindle assembly checkpoint analysis by standard nocodazole-challenge assay. Mitotic arrest duration of PtenΔTKV /ΔTKV and Dlg1−/− MEFs after nocodazole addition. n = 3 MEF lines per genotype (8–26 cells per line). (c–f) Error correction machinery analysis in PtenΔTKV /ΔTKV MEFs. (c) Western blot analysis of mitotic lysates of WT and PtenΔTKV /ΔTKV MEFs immunoblotted for Aurora B and p-Aurora, demonstrating that this core component of this machinery was normally expressed and activated in mitosis. P-histone H3 (p-H3) served as a control for equal loading of mitotic cells. (d) Quantitation of p-Aurora B kinase signals at inner centromeres in prometaphase MEFs, demonstrating proper Aurora B in PtenΔTKV /ΔTKV MEFs. n = 3 independent cell lines (10 cells per line). (e,f) Quantitation of two key kinetochore-associated substrates of Aurora B, p-Knl1 (e) and p-CenpA (f), further indicating that error correction was normal in cells lacking the Pten PDZ-BD. n = the number of independent MEF lines (12–20 cells per line). (g) Incidence of MEFs with centrosome distance ≥3 μm in G2 as a measure for early centrosome separation. Costaining with p-Histone H3 served to identify cells in G2 phase. n = 3 independent MEF lines (20 cells per line). (h) Analysis of planar spindle orientation. n = 3 independent MEF lines (10 cells per line). Data in a, d–h represent mean ± s.e.m. and in b represent mean ± s.d. Statistical significance was determined by a two-tailed unpaired t-test. Unprocessed original scans of blots can be found in Supplementary Fig. 6 and Statistics Source Data in Supplementary Table 1.

Supplementary Figure 3 WT MEFs subjected to partial Eg5 inhibition have similar chromosome segregation errors as PtenΔTKV /ΔTKV and Dlg1−/− MEFs.

(a) Quantification of Eg5 signal at astral microtubules and centrosomes at various mitotic stages. n = 15 MEFs per mitotic stage per genotype. (b) Quantitation of Kif15 signals at centrosomes. The analysis was done on n = 3 independent MEF lines per genotype (5 cells per line). (c) Images of HT1299 prophase cells immunostained for EG5 and γ-tubulin 72 h after transduction with the indicated shRNA lentiviruses (bar, 5 μm). Quantitation of EG5 signals at centrosomes for n = 3 independent immunostaining experiments (10-15 cells per experiment). (d) Analysis of complex formation between endogenous PTEN, DLG1 and EG5 in mitotic HeLa cells by reciprocal co-immunoprecipitation assays. Blots are representative of 2 independent experiments. (e) WT MEFs treated with indicated amount of monastrol monitored for mitotic defects by live-cell imaging as they progress through mitosis. The analysis was performed on n = 5 independent MEF lines (>13–37 cells per line). (f–h) APC/CCdh1 assembly is unperturbed in PtenΔTKV /ΔTKV cells. (f) Immunoblots of mitotic WT and PtenΔTKV /ΔTKV MEF lysates subjected to immunoprecipitation with Cdc27 or control (IgG) antibodies and analyzed by western blotting with Cdh1 and Cdc27 antibodies. Blots are representative for 3 independent experiments. (g) Western blot analysis of mitotic MEF lysates for p-PtenS380. Phosphorylation of S380 by Plk1 during mitosis controls Pten association with Cdh118: this regulatory mechanism is unperturbed when the Pten PDZ-BD is lacking. (h) Western blot analysis of mitotic lysates of WT and PtenΔTKV /ΔTKV MEFs for select mitotic substrates that are subject to degradation by APC/CCdh1. Pon S staining of blotted proteins served as a loading control. Data in a–c, e represent mean ± s.e.m. Statistical significance in a and b was determined by a two-tailed unpaired t-test, in c by a one-sample t-test against a theoretical mean of unity, and in e by a two-tailed paired t-test. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. Unprocessed original scans of blots can be found in Supplementary Fig. 6 and Statistics Source Data in Supplementary Table 1.

Supplementary Figure 4 DLG1-mediated docking of EG5 to PTEN at centrosomes is dependent on NEK9-NEK6 and cyclin B1-CDK1 kinase activity.

(a) Immunoblots of mitotic HT1299 or HeLa extracts subjected to immunoprecipitation with PTEN antibody or control IgG and analyzed with the indicated antibodies. Blots are representative for 2 independent experiments. (b) Western blots of lysates from HT1299 cells transduced with NEK6 or NEK9 shRNA or non-silencing shRNA negative control (Con) lentiviruses and analyzed 72 h later. (c) Prophase cells stained for p-NEK9T210 after transduction with NEK9 shRNA or non-silencing control shRNA. Centrosome-associated p-NEK9T210 was quantified. (d) As c stained for EG5. Centrosome-associated EG5 was quantified. (e) Prophase cells stained for p-NEK9T210 after transduction with PTEN shRNA or non-silencing control shRNA. Centrosome-associated p-NEK9T210 was quantified. (f) As cstained for DLG1. Centrosome-associated DLG1 was quantified. (g) Prophase cells stained for p-NEK9T210 after transduction with NEK6 shRNA or non-silencing control shRNA. Centrosome-associated p-NEK9T210 was quantified. (h) As g stained for EG5. Centrosome-associated EG5 was quantified. (i,j) As g stained for DLG1. Centrosome-associated DLG1 was quantified. (k) Prophase cells transiently expressing Myc-tagged WT or mutant EG5 immunostained for ectopic EG5. (l) As i but for prophase cells depleted for CCNB1. All data presented are mean ± s.e.m. n = 3 independent experiments in d–f, h–j and l (10–18 cells per condition) and n = 10 cells in c and g. Statistical significance in d,e and h was determined by a one-sample t-test against a theoretical mean of unity, in c and g by an unpaired t-test and in f,i,j and l by a two-tailed paired t-test. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. Unprocessed original scans of blots can be found in Supplementary Fig. 6 and Statistics Source Data in Supplementary Table 1.

Supplementary Figure 5 Partial Pten PDZ-BD loss perturbs spindle assembly and cause chromosome missegregation.

(a) Immunoblots of mitotic MEF extracts precipitated with indicated antibodies and analyzed for Dlg1 (representative for 2 experiments). (b) Relative Pten-Dlg1 complex formation (mean of 2 independent experiments). (c) MEFs analyzed for mitotic defects. n = the number of independent MEF lines (29–71 cells/line). (d) Karyotyping of MEFs and splenocytes from 5-month-old mice. n = the number of independent MEF lines or spleens (50 spreads/MEF line or spleen). (e) Western blots of lysates from indicated tissues of WT and Pten+/ΔTKV mice. (f) Incidence of spindle asymmetry. n = the number of independent MEF lines (20 cells/line). (g) Incidence of prophases with reduced centrosome movement. n = 3 independent MEF lines (20 cells/line). (h) Monopolar spindle formation in 16.6 μM monastrol. n = 3 independent MEF lines (64–95 cells/line). (i) Quantification of Eg5 signal at astral microtubules and centrosomes in prophase. n = 3 independent MEF lines/genotype (10 cells/line). (j) Overall survival curves showing that PtenΔTKV /ΔTKV lifespan is shortened. (k) Survival curves of WT and PtenΔTKV /ΔTKV mice dying with tumors showing that PtenΔTKV /ΔTKV mice develop tumors faster, although the overall tumor incidence was unchanged (66% in WT versus 67% in PtenΔTKV /ΔTKV mice). The tumor spectrum of both WT and PtenΔTKV /ΔTKV mice consisted of lymphomas, sarcomas, and liver and lung tumors. Of these, the incidence of lymphomas was significantly increased in PtenΔTKV /ΔTKV mice (50% versus 32% in WT mice). (l) Survival curves of mice dying with lymphoma showing that lymphomas are not only more prevalent in PtenΔTKV /ΔTKV mice, but also develop faster. WT and PtenΔTKV /ΔTKV values in f and g were taken from Fig. 2f, h. Data shown in b,d,f and g are the mean ± s.d., in c,h and i the mean ± s.e.m. Statistical significance in c,d,f–h was determined by unpaired t-test, and in b,i by a one-sample t-test against a theoretical mean of unity, and by Log-rank tests in j–l. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. See Supplementary Fig. 6 for unprocessed blot scans and Supplementary Table 1 for Statistics Source Data.

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van Ree, J., Nam, HJ., Jeganathan, K. et al. Pten regulates spindle pole movement through Dlg1-mediated recruitment of Eg5 to centrosomes. Nat Cell Biol 18, 814–821 (2016). https://doi.org/10.1038/ncb3369

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