The term ‘casein kinase’ has been widely used for decades to denote protein kinases sharing the ability to readily phosphorylate casein in vitro. These fall into three main classes: two of them, later renamed as protein kinases CK1 (casein kinase 1, also known as CKI) and CK2 (also known as CKII), are pleiotropic members of the kinome functionally unrelated to casein, whereas G-CK, or genuine casein kinase, responsible for the phosphorylation of casein in the Golgi apparatus of the lactating mammary gland, has only been identified recently with Fam20C [family with sequence similarity 20C; also known as DMP-4 (dentin matrix protein-4)], a member of the four-jointed family of atypical protein kinases, being responsible for the phosphorylation of many secreted proteins. In hindsight, therefore, the term ‘casein kinase’ is misleading in every instance; in the case of CK1 and CK2, it is because casein is not a physiological substrate, and in the case of G-CK/Fam20C/DMP-4, it is because casein is just one out of a plethora of its targets, and a rather marginal one at that. Strikingly, casein kinases altogether, albeit representing a minimal proportion of the whole kinome, appear to be responsible for the generation of up to 40–50% of non-redundant phosphosites currently retrieved in human phosphopeptides database. In the present review, a short historical explanation will be provided accounting for the usage of the same misnomer to denote three unrelated classes of protein kinases, together with an update of our current knowledge of these pleiotropic enzymes, sharing the same misnomer while playing very distinct biological roles.

Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr(F508del) homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

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The blooming of nanotechnology has made available a limitless landscape of solutions responding to crucial issues in many fields and, nowadays, a wide choice of nanotechnology-based strategies can be adopted to circumvent the limitations of conventional therapies for cancer. Herein, the current stage of nanotechnological applications for cancer management is summarized encompassing the core nanomaterials as well as the available chemical–physical approaches for their surface functionalization and drug ligands as possible therapeutic agents. The use of nanomaterials as vehicles to delivery various therapeutic substances is reported emphasizing advantages, such as the high drug loading, the enhancement of the pay-load half-life and bioavailability. Particular attention was dedicated to highlight the importance of nanomaterial intrinsic features. Indeed, the ability of combining the properties of the transported drug with the ones of the nano-sized carrier can lead to multifunctional theranostic tools. In this view, fluorescence of carbon quantum dots, optical properties of gold nanoparticle and superparamagnetism of iron oxide nanoparticles, are fundamental examples. Furthermore, smart anticancer devices can be developed by conjugating enzymes to nanoparticles, as in the case of bovine serum amine oxidase (BSAO) and gold nanoparticles. The present review is aimed at providing an overall vision on nanotechnological strategies to face the threat of human cancer, comprising opportunities and challenges.

It has been reported that pyrvinium pamoate (PyrPam), an FDA (U.S. Food and Drug Administration)-approved anthelminthic drug, is a potent inhibitor of Wnt signalling by a mechanism which implies the direct activation of protein kinase CK1α. In the present paper, we provide data ruling out any direct stimulatory effect of PyrPam on CK1, by showing that the catalytic activity of CK1α and those of its isoforms δ and γ1 are not significantly affected by PyrPam when tested with the aid of specific peptide and protein substrates. Accordingly, cell treatment with PyrPam has no significant effect on the phosphorylation of β-catenin Ser45. By contrast, the phosphorylation of β-catenin Thr41 is increased upon cell treatment with PyrPam, through a mechanism that implies the upstream dephosphorylation of Akt/PKB (protein kinase B) and of GSK3 (glycogen synthase kinase 3). It can be concluded from the present study that PyrPam is not a bona fide activator of CK1, its perturbation of cell signalling pathways being mediated by a complex mechanism initiated by a fall in Akt phosphorylation whose down-regulation promotes reduced phosphorylation and activation of GSK3. Consistent with this, lysates of cells treated with PyrPam display enhanced protein phosphorylation which is unaffected by CK1 inhibition, while disappearing upon inhibition of GSK3. Our data are consistent with the observation that PyrPam ultimately inhibits Wnt signalling despite its lack of efficacy on CK1.