PTEN regulates PLK1 and controls chromosomal stability during cell division

Abstract

PTEN functions as a guardian of the genome through multiple mechanisms. We have previously established that PTEN maintains the structural integrity of chromosomes. In this report, we demonstrate a fundamental role of PTEN in controlling chromosome inheritance to prevent gross genomic alterations. Disruption of PTEN or depletion of PTEN protein phosphatase activity causes abnormal chromosome content, manifested by enlarged or polyploid nuclei. We further identify polo-like kinase 1 (PLK1) as a substrate of PTEN phosphatase. PTEN can physically associate with PLK1 and reduce PLK1 phosphorylation in a phosphatase-dependent manner. We show that PTEN deficiency leads to PLK1 phosphorylation and that a phospho-mimicking PLK1 mutant causes polyploidy, imitating functional deficiency of PTEN phosphatase. Inhibition of PLK1 activity or overexpression of a non-phosphorylatable PLK1 mutant reduces the polyploid cell population. These data reveal a new mechanism by which PTEN controls genomic stability during cell division.

Targeted treatment for glioblastoma: Revisiting conventional strategies and novel targets

“…Sitoplazma bulunan PTEN, sahip olduğu fosfataz aktivitesi ile fosfatidilinositol 3-kinaz (PI3K) sinyal iletim yolunun en önem-li negatif düzenleyicisi olarak görev yapar. Öte yandan, hücre çekirdeği içerisindeki PTEN ise kromozom stabilitesinin düzenlenmesinde (39) , DNA tamirinde (40) ve apoptotik hücre ölümünün düzenlenmesinde görev alır (41,42) .…”

Unmasking PTEN's nuclear functions

“…A couple of elegant studies by the Shen laboratory have led to the identification of mitotic substrates of PTEN that play an essential role in mediating chromosome congression and segregation during mitosis. 5,6 Through affinity purification and mass spectrometry, Zhang et al has found that polo-like kinase 1 (Plk1) is a PTEN-interacting protein with peak interaction at mitosis. 5 In a separate study, He et al in the same research group demonstrated that PTEN is physically associated with EG5, a mitotic motor protein involved in regulating spindle architecture and pole integrity.…”

“…5,6 Through affinity purification and mass spectrometry, Zhang et al has found that polo-like kinase 1 (Plk1) is a PTEN-interacting protein with peak interaction at mitosis. 5 In a separate study, He et al in the same research group demonstrated that PTEN is physically associated with EG5, a mitotic motor protein involved in regulating spindle architecture and pole integrity. 6 The physical interaction between PTEN and Plk1 has been demonstrated early.…”

“…This research team has observed that PTEN deficiency resulted in hyperphosphorylation of Plk1 and EG5; subsequently, these researchers have demonstrated that PTEN directly dephosphorylates Plk1 and EG5, thereby either reducing Plk1 activity or causing aberrant subcellular localization of EG5. 5,6 To further confirm that Plk1's phosphorylation status depends on PTEN phosphatase activity, these researchers have made use of Pten ¡/¡ MEFs that have been transfected with wild-type PTEN or individual phosphatase-deficient mutants. They have demonstrated that Pten null cells contain elevated levels of both phospho-Plk1 (T210) and Plk1, which is suppressed by ectopic expression of wild-type PTEN and PTEN G129E , the latter being a mutant that primarily affects the activity of protein phosphatase but not lipid phosphatase of PTEN.…”

“…In contrast, expression of non-phosphorylatable Plk1 or treatment of Plk1-specific inhibitor BI2536 suppresses chromosomal instability. 5 Likewise, PTEN-deficiency abrogates EG5 recruitment to the mitotic spindle apparatus, causing spindle disorganization; these phenotypes can be corrected by expression of PTEN and phosphorylation-resistant EG5 mutant. 6 A clear regulatory network that explains the function of nuclear PTEN has emerged from these 2 studies.…”