Plk5, a Polo Box Domain-Only Protein with Specific Roles in Neuron Differentiation and Glioblastoma Suppression

Abstract

Polo-like kinases (Plks) are characterized by the presence of a specific domain, known as the polo box (PBD), involved in protein-protein interactions. Plk1 to Plk4 are involved in centrosome biology as well as the regulation of mitosis, cytokinesis, and cell cycle checkpoints in response to genotoxic stress. We have analyzed here the new member of the vertebrate family, Plk5, a protein that lacks the kinase domain in humans. Plk5 does not seem to have a role in cell cycle progression; in fact, it is downregulated in proliferating cells and accumulates in quiescent cells. This protein is mostly expressed in the brain of both mice and humans, and it modulates the formation of neuritic processes upon stimulation of the brain-derived neurotrophic factor (BDNF)/nerve growth factor (NGF)-Ras pathway in neurons. The human PLK5 gene is significantly silenced in astrocytoma and glioblastoma multiforme by promoter hypermethylation, suggesting a tumor suppressor function for this gene. Indeed, overexpression of Plk5 has potent apoptotic effects in these tumor cells. Thus, Plk5 seems to have evolved as a kinase-deficient PBD-containing protein with nervous system-specific functions and tumor suppressor activity in brain cancer.

The Polo-Like Kinase PLKA in Aspergillus nidulans Is Not Essential but Plays Important Roles during Vegetative Growth and Development

“…While interphase cells contained normal cytoplasmic arrays ( Fig. 4A and C), 16.4% of the mitotic ⌬plkA cells showed abnormal spindles, including bent, monopolar, or frayed arrangements ( Fig. 4E and F), compared to 0 to 2.0% in control cells (Table 4).…”

“…For example, PLK1 and Polo phosphorylate factors that influence asymmetric cell divisions and cell fate determinants in worms and flies (56,71), Polo activates meiosis in the fly oocyte (39), and PLK2 is required for neuron differentiation in mice (19). Human PLK5 has no known cell cycle function but is specifically expressed in glial and neuronal cells and is also important for neuronal development (16). Fungal Plks, however, have not demonstrated cell cycle-independent roles in development to date.…”

“…The PBD is typically composed of two polo box motifs, but the divergent and less characterized PLK4 contains a single canonical PBD motif as well as a cryptic polo box sequence (4,35). Human PLK5, on the other hand, contains a normal PBD but lacks the catalytic domain (16).…”

“…Metazoans contain several Plk homologues, including Polo and PLK4 in Drosophila melanogaster, PLK1 to PLK3 in Caenorhabditis elegans, Plx1 to Plx3 in Xenopus laevis, and PLK1, PLK2/SNK, PLK3/FNK/PRK, PLK4/SAK, and PLK5 in mammals (3,4,16). Single Plks exist in fungal species, including Plo1 in Schizosaccharomyces pombe (45), Cdc5p in Saccharomyces cerevisiae (30), Cdc5p in Candida albicans (6), and PLKA in Aspergillus nidulans (5).…”

Polo-like Kinase 1 as a Target for Anti-tumor Therapy

“…Zvýšená hladina Plk1 se vyskytuje také u nádorů prsu [43][44][45], jater [46], slinivky [47,48], prostaty [49], stejně tak jako u kolorektálního karcinomu [11,50], nádorů enních, jako např. mozeček, a její exprese je epigeneticky umlčena u glioblastomů [15,16]. Komplexní a podrobnější informace o jednotlivých členech proteinů rodiny Plk lze najít v přehledovém článku De Cárcer et al [15].…”