Disease relevance of PLK4

• In Staphylococcus aureus phages encoding immune evasion molecules (SAK, SCIN, CHIPS), which integrate specifically into the beta-haemolysin (Hlb) gene, are widely distributed [1].
• Comparative expression of the mitotic regulators SAK and PLK in colorectal cancer [2].

High impact information on PLK4

• The majority of spermatids in SAK mutants lack centrioles and so are unable to make sperm axonemes [3].
• Human cells depleted of SAK show error-prone mitosis, likely to underlie its tumor-suppressor role [3].
• RESULTS: Here, we show that downregulation of SAK in Drosophila cells, by mutation or RNAi, leads to loss of centrioles, the core structures of centrosomes [3].
• SAK-/- mice die during embryogenesis, whereas SAK+/- mice develop liver and lung tumors and SAK+/- MEFs show mitotic abnormalities [3].
• We also show that SAK mutants lose their centrioles during the mitotic divisions preceding male meiosis but still produce cysts of 16 primary spermatocytes as in the wild-type [3].

Biological context of PLK4

• Although Sak protein is presumed to be involved in cell growth mechanism, efforts have failed to demonstrate its kinase activity [4].
• Little has been, therefore, elucidated how Sak is regulated and how Sak contributes to cell proliferation [4].
• SAK, a new polo-like kinase, is transcriptionally repressed by p53 and induces apoptosis upon RNAi silencing [5].
• Using in vitro kinase assays on peptide spots arrays, we determined the consensus phosphorylation motif for Sak to be yen-[Ile/Leu/Val]-Ser/Thr-varphi-varphi-X- yen/Pro (where varphi denotes a large hydrophobic residue, yen is a charged residue dependent on the context of the surrounding sequence, and residues in brackets are unfavoured) [6].
• The predicted protein sequences of Rab7a and Rab7b contain all characteristic domains essential for Rab function: the effector domain (YRATVGADF) and four GTP-binding consensus sequences (GDSGVGKT, WDTAGQ, NKLD, SAK) as well as the prenylation motif (-CC) at the C-terminus indispensable for Rab binding to the membrane [7].

Anatomical context of PLK4

• Finally, we show that depletion of SAK in human cells also prevents centriole duplication and gives rise to mitotic abnormalities [3].
• Levels of SAK and PLK expression in tumor relative to paired normal mucosa correlated directly with patient age and with each other but did not correlate with tumor stage [2].
• RESULTS: In the majority of cases, both SAK and PLK were more highly expressed in tumor tissue than in adjacent normal intestinal mucosa [2].

Associations of PLK4 with chemical compounds

• SAK and PLK are members of the polo family of serine threonine kinases, which in lower organisms have been shown to be required for the precise regulation of mitosis [2].
• CD spectra of polycationic (SAK, OAK), amphoteric (EAK), or polyanionic (Ac-EAK) polylysine derivatives were recorded in 0.25M acetate buffer at pH 7.4 as well as in the presence of DPPC or DPPC/PG (95/5, 80/20 mol/mol) liposomes [8].

Regulatory relationships of PLK4

• Further characterization revealed that SAK expression was downregulated by wild-type p53 in several tumor cell models [5].

Other interactions of PLK4

• Biologically, SAK RNA interference (RNAi) silencing induced apoptosis, whereas SAK overexpression attenuated p53-induced apoptosis [5].
• This consensus phosphorylation motif differs from that of Plk1, and provides a basis for future studies to identify in vivo substrates of Sak [6].

Analytical, diagnostic and therapeutic context of PLK4

• The intensity of ELISA reaction was highest against the recombinant fusion antigen GSTBP22; the chemically conjugated SAK-BP22 performed less well than the free dimeric form of the peptide [9].

References