Polo-like kinase (Plk1) substrates and mitosis

Polo-like kinase (Plk1) substrates and mitosis

Polo-like kinase (Plk1)

Polo-like kinase (Plk1), is a serine/threonine kinase that is active during mitosis (Hamanaka et al., 1995). Its name is derived from its original characterisation as a homolog of a Drosophila mitotic kinase encoded by the Polo gene (Fenton et al., 1993; Martin et al., 2006). There are five Plk kinases identified in humans, although only Plk1 has been extensively characterised as a mitotic kinase (Martin et al., 2006; Lens et al., 2010).

Polo-like Kinase family members

Other members of the family have largely non-mitotic functions: Plk2 and Plk4 are involved in centriole duplication (Warnke et al., 2004; Habedanck et al., 2005), while Plk3 is implicated in p53-dependent stress responses (Xie et al., 2001). Plk5 is thought to be enzymatically inactive in humans (Lens et al., 2010). Plk1 has been found to orchestrate numerous essential processes during mitosis (Van Vugt et al., 2005).

Plk1 regulates Mitotic exit

Plk1 regulates mitotic exit by phosphorylating and inhibiting early mitotic inhibitor-1 (Emi1). Emi1 itself inhibits the APC/C, so Plk1 phosphorylation of Emi is necessary for progression into anaphase (Moshe et al., 2004). On the other hand, Plk1 also regulates mitotic entry. Plk1 enhances the activation of cyclin B by at least 3 distinct mechanisms. Firstly, Plk1 phosphorylates and activates the Cdc25 phosphatase, inducing the removal of an inhibitory phosphorylation from Cdk1/cyclin B (Roshak et al., 2000).

Plk1 phosphorylates Wee1 & Myt1

Secondly, Plk1 phosphorylation of wee1 and myt1, tyrosine kinase inhibitors of Cdk1, inhibits myt1 activity (Inoue et al., 2005), and induces degradation of wee1 (Watanabe et al., 2004), allowing Cdk1 activation and mitotic entry. Finally, Plk1 can directly phosphorylate cyclin B, regulating its translocation to the nucleus during prophase (Toyoshima-Morimoto et al., 2001; Yuan et al., 2002). Plk1 regulates the accumulation of numerous components to the mitotic spindle. One report identified 358 unique Plk1-dependent phosphorylation sites on spindle proteins via a phosphoproteomic screen (Santamaria et al., 2011). It was also demonstrated that Plk1 inactivation led to the loss of at least 64 proteins from the spindle, including Aurora kinase A and mxd1, highlighting the importance of Plk1 activity in spindle recruitment.

Plk1 is upregulated in cancer

Plk1 has been shown to be upregulated in numerous cancers, such as squamous cell carcinomas (Knecht et al., 1999) and non-small cell lung cancer (Wolf et al., 1997), and to be essential for mitosis in cancer cells, with Plk1 depletion leading to mitotic arrest and subsequent apoptosis (Liu et al., 2003). Similar depletion of Plk1 in untransformed cells was not found to result in apoptosis (Liu et al., 2006).

Polo box domain (PBD)

Plk1 contains a regulatory C-terminal region known as the Polo box domain (PBD). When the PBD is not engaged by interaction with a recognised substrate, it binds to the Plk1 catalytic domain (Jang et al., 2002), and prevents catalytic activity of the enzyme. This auto-inhibitory mechanism prevents non-specific Plk1 kinase activity. The PBD also facilitates the attachment of Plk1 to microtubules during interphase, by binding to the microtubule-associated protein MAP205 (Archambault et al., 2008). The PBD recognises and interacts with phosphoserine/phosphothreonine residues followed by an immediately adjacent proline residue (Elia et al., 2003; Elia et al., 2003b).

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18th Dec 2020 Sean Mac Fhearraigh

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