Mammalian polo-like kinases (Plks) are characterized by the presence of an N-terminal protein kinase domain and a C-terminal polo-box domain (PBD) involved in substrate binding and regulation of kinase activity. Plk1-4 have traditionally been linked to cell cycle progression, genotoxic stress and, more recently, neuron biology. Recently, a fifth mammalian Plk family member, Plk5, has been characterized in murine and human cells. Plk5 is expressed mainly in differentiated tissues such as the cerebellum. Despite apparent loss of catalytic activity and a stop codon in the middle of the human gene, Plk5 proteins retain important functions in neuron biology. Notably, its expression is silenced by epigenetic alterations in brain tumors, such as glioblastomas, and its re-expression prevents cell proliferation of these tumor cells. In this review, we will focus on the non-cell cycle roles of Plks, the biology of the new member of the family and the possible kinase- and PBD-independent functions of polo-like kinases.

An increasing number of independent studies indicate that the atypical protein kinase C (PKC) isoforms (aPKCs) are critically involved in the control of cell proliferation and survival. The aPKCs are targets of important lipid mediators such as ceramide and the products of the PI 3-kinase. In addition, the aPKCs have been shown to interact with Ras and with two novel proteins, LIP (lambda-interacting protein; a selective activator of λ/ιPKC) and the product ofpar-4 (a gene induced during apoptosis), which is an inhibitor of both λ/ιPKC and ζPKC. LIP and Par-4 interact with the zinc finger domain of the aPKCs where the lipid mediators have been shown to bind. Here we report the identification of p62, a previously described phosphotyrosine-independent p56^lckSH2-interacting protein, as a molecule that interacts potently with the V1 domain of λ/ιPKC and, albeit with lower affinity, with ζPKC. We also show in this study that ectopically expressed p62 colocalizes perfectly with both λ/ιPKC and ζPKC. Interestingly, the endogenous p62, like the ectopically expressed protein, displays a punctate vesicular pattern and clearly colocalizes with endogenous λ/ιPKC and endogenous ζPKC. P62 colocalizes with Rab7 and partially with lamp-1 and limp-II as well as with the epidermal growth factor (EGF) receptor in activated cells, but not with Rab5 or the transferrin receptor. Of functional relevance, expression of dominant negative λ/ιPKC, but not of the wild-type enzyme, severely impairs the endocytic membrane transport of the EGF receptor with no effect on the transferrin receptor. These findings strongly suggest that the aPKCs are anchored by p62 in the lysosome-targeted endosomal compartment, which seems critical for the control of the growth factor receptor trafficking. This is particularly relevant in light of the role played by the aPKCs in mitogenic cell signaling events.

Tumor cell proliferation is frequently associated with genetic or epigenetic alterations in key regulators of the cell cycle. Most known oncogenes and tumor suppressors target entry into the cell cycle and control the G₁/S transition. However, tumor-associated alterations in spindle formation or chromosome segregation are also frequent and may result in chromosomal instability. In fact, a few centrosomal or mitotic proteins such as aurora A, polo-like kinase 1 and PTTG1 (securin) have been reported to act as oncogenes. Some spindle checkpoint regulators such as the BUB kinases or MAD2 protect cells from aberrant chromosome segregation and may therefore function as suppressors of malignant transformation. However, few cancer-associated mutations in these or other mitotic regulators have been described thus far and many of these molecules do not fit into the classical definition of ‘oncogenes’ or ‘tumor suppressor genes’. In some cases, both over-expression and decreased expression of these genes result in mitotic arrest. Moreover, some mitotic regulators such as MAD2 are either up- or down-regulated depending on the tumor types and, in both cases, these alterations result in chromosomal imbalances and tumor development. Minor changes in protein levels that do not compromise cell viability might therefore be sufficient to dysregulate the mitotic cycle and induce genomic instability. Despite the limited knowledge on the molecular basis of these processes, the clinical success of mitotic poisons such as taxanes reinforces the interest in these molecules, their involvement in human cancer and the therapeutic opportunities to modulate their function in cancer treatment.

Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression results in abnormal chromosome segregation and cytokinesis, generating polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge, in a Plk1 kinase-dependent manner. In vivo, Plk1 overexpression prevents the development of Kras-induced and Her2-induced mammary gland tumors, in the presence of increased rates of chromosome instability. In patients, Plk1 overexpression correlates with improved survival in specific breast cancer subtypes. Therefore, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor-suppressive properties by perturbing mitotic progression and cytokinesis.