Protein phosphatase 2A (PP2A) is a family of multifunctional serine/threonine phosphatases all composed of a catalytic C, a structural A, and a regulatory B subunit. Assembly of the complex with the appropriate B subunit forms the key to the functional specificity and regulation of PP2A. Emerging evidence suggests a crucial role for methylation and phosphorylation of the PP2A C subunit in this process. In this study, we show that PP2A C subunit methylation was not absolutely required for binding the PR61/B and PR72/B؆ subunit families, whereas binding of the PR55/B subunit family was determined by methylation and the nature of the C-terminal amino acid side chain. Moreover mutation of the phosphorylatable Tyr 307 or Thr 304 residues differentially affected binding of distinct B subunit family members. Down-regulation of the PP2A methyltransferase LCMT1 by RNA interference gradually reduced the cellular amount of methylated C subunit and induced a dynamic redistribution of the remaining methylated PP2A C between different PP2A trimers consistent with their methylation requirements. Persistent knockdown of LCMT1 eventually resulted in specific degradation of the PR55/B subunit and apoptotic cell death. Together these results establish a crucial foundation for understanding PP2A regulatory subunit selection.Protein phosphatase 2A (PP2A) 2 represents a family of heterotrimeric serine/threonine phosphatases implicated in the regulation of a plethora of cellular processes such as apoptosis, transcription, translation, DNA replication, signal transduction, protection against tumorigenesis, and cell division (for reviews, see Refs. 1 and 2). It is estimated that, depending on the cell type, PP2A holoenzymes are responsible for 30 -50% of the total cellular serine/threonine dephosphorylating activity, demonstrating the importance of this enzyme system for almost any aspect of life.The basis of this broad functional importance is formed by the diversity of specific PP2A subunit compositions. Typically the PP2A core enzyme exists as a dimer (PP2A D ) consisting of a catalytic subunit (C subunit/PP2A C ) and a scaffolding A subunit (PR65/A subunit). Proper functioning and regulation of PP2A is achieved by the association of regulatory B subunits 3 with the PP2A core enzyme, resulting in the formation of heterotrimeric PP2A holoenzymes with specific catalytic properties, subcellular locations, and substrate specificities. At present, three multigene families of B-type subunits have been described, PR55/B, PR61/BЈ, and PR72/BЉ, all with specific cellular functions. Therefore, the assembly of the complex with the appropriate B-type subunit is the key to specificity and regulation of PP2A (2). In this process, the highly conserved C-terminal PP2A C tail seems to play a crucial role (3, 4). Recently a major breakthrough has been achieved by elucidating the crystal structure of a heterotrimeric PP2A T61␥ holoenzyme (5, 6). It was shown that the C-terminal PP2A C tail recognizes a surface groove at the interface between the PR65 a...

Over the last decades, advances in the knowledge of immunology have led to the identification of immune checkpoints, reinvigorating cancer immunotherapy. Although normally restricted to activated T and B cells, constitutive expression of CD70 in tumor cells has been described. Moreover, CD70 is implicated in tumor cell and regulatory T cell survival through interaction with its ligand, CD27. In this review, we summarize the targetable expression patterns of CD70 in a wide range of malignancies and the promising mechanism of anti-CD70 therapy in stimulating the anti-tumor immune response. In addition, we will discuss clinical data and future combination strategies.

In the last decades the approach to cancer patient management has been deeply revolutionized. We are moving from a "one-fits-all" strategy to the "personalized medicine" based on the molecular characterization of the tumor. In this new era it is becoming more and more clear that the monitoring of the disease is fundamental for the success of the treatment, thus there is the need of new biomarker discovery. More precisely in the last years the scientific community has started to use the term "liquid biopsy". A liquid biopsy is a liquid biomarker that can be easily isolated from many body fluids (blood, saliva, urine, ascites, pleural effusion, etc.) and, as well as a tissue biopsy, a representative of the tissue from which it is spread. In this review we will focus our attention on circulating tumor cells, circulating tumor DNA, exosomes and secretomes with the aim to underlie their usefulness and potential application in a clinical setting for lung cancer patient management.

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