Haploid germ cell specific nuclear protein kinase Haspin

Haploid germ cell-specific nuclear protein kinase (Haspin) proteins are divergent members of the eukaryotic protein kinase family. Haspin (encoded by germ cell-specific gene 2: Gsg2) is found in many eukaryotic lineages (animal, fungi, and plants), and the protein and its mRNA were initially detected in male germ VUF 11207 fumarate [4]. All proliferating cell lines express Haspin mRNA, and it has been detected in thymus, bone marrow, and foetal liver and, more weakly, in spleen, intestine, lung, and a variety of fetal tissues. Its expression is correlated with tissues that have significant levels of cellular proliferation and differentiation [5]. Studies have confirmed Haspin as a serine/threonine kinase and a constitutively active enzyme. Studies have shown that, during interphase, Haspin is autoinhibited by a conserved segment of basic residues (the Haspin basic inhibitory segment; HBIS) within the N-terminal domain, immediately upstream of the kinase domain. The kinase is reactivated in M phase by Cdk1 phosphorylation of the N terminus (Fig. 1). This phosphorylation leads to recruitment of Polo-like kinase-1 (Plk-1), which in turn further phosphorylates multiple sites at the N-terminal domain of Haspin. In addition, in human cells, the localisation of Aurora B kinase to the centromere creates a positive feedback loop that increases Haspin activity [6]. The crystal structure of Haspin reveals at least four peculiarities [5]: (i) the N-terminal lobe is entirely buried under an additional layer created by an N-terminal extension and two insertions; (ii) reorganisation of the activation segment contributes to the creation of an unusual substrate-binding site; (iii) an additional insertion between the β7 and β8 loop that contains two β-strands; and (iv) deletion of the αG helix. During mitosis, Haspin localises predominantly to condensed chromosomes during mitosis, to centrosomes following nuclear envelope breakdown (NEBD), to spindle microtubules during metaphase, and to the midbody during telophase. The only know substrate of Haspin is histone H3. During mitosis, Haspin phosphorylates histone H3 at threonine 3 to form H3T3ph [7]. Phosphorylated threonine 3 is detected on condensing chromosomes during prophase, prometaphase, and metaphase, is decreased during anaphase and is absent during telophase. Histone H3T3ph creates a chromatin-binding site for survivin and recruits the chromosomal passenger complex (CPC; see Glossary) at inner centromeres during mitosis 8, 9, 10, 11, 12. Haspin activity facilities the activation of Aurora B, a member of the CPC (Fig. 2). Aurora B kinase activity is necessary for full phosphorylation of Haspin during mitosis and stimulates H3T3 phosphorylation. It also acts to generate a positive feedback between Haspin and Aurora B and allows CPC accumulation on chromatin during mitosis [13]. The complex protein phosphatase 1γ(PP1γ)/Repo-Man induces indirect inhibition of Haspin by dephosphorylating of H3T3 at the end of mitosis 14, 15. Haspin overexpression or deletion results in defective mitosis. Inhibition of Haspin prevents normal chromosome alignment at metaphase, while Haspin overexpression results in a delay before metaphase. In addition, Haspin depletion leads to the loss of the cohesion association and activation of the spindle checkpoint, arresting mitosis in a prometaphase-like state [16]. Haspin inhibitors have antimitotic effects and might have fewer adverse effects than many other kinase inhibitors currently used as therapeutics because Haspin has only one known substrate (Thr 3 of histone 3) [17]. A previous study showed that Haspin inhibitors cause the displacement of Aurora B from inner centromeres, resulting in its diffuse distribution on chromatin [17] many other kinase inhibitors currently used as therapeutics.
Haspin inhibitors
Concluding remarks The cell cycle is an elaborate and evolutionarily conserved process in actively proliferating cells. Given that cell cycle aberrations are a hallmark of cancer, mitosis has been the target of anticancer strategies for decades; however, despite numerous mitosis-selective drug discovery strategies (e.g., microtubule-targeting agents, antimitotic kinases, and antimotor proteins; Table 1) and ensuing clinical trials, mitosis-targeted anticancer therapies have generally failed to translate their preclinical efficacy into clinical responses in human trials owing, in particular, to undesirable effects on nonproliferating cells and the emergence of drug resistance.