The reversible phosphorylation of proteins plays hugely important roles in a variety of cellular processes, such as differentiation, proliferation, and apoptosis. These processes are strictly controlled by protein kinases (phosphorylation) and phosphatases (de-phosphorylation). Here we provide a brief history of the study of protein phosphorylation, including a summary of different types of protein kinases and phosphatases. One of the most physiologically important serine/threonine phosphatases is PP2A. This review provides a description of the phenotypes of various PP2A transgenic mice and further focuses on the known functions of PP2A in bone formation, including its role in osteoblast differentiation and function. A reduction in PP2A promotes bone formation and osteoblast differentiation through the regulation of bone-related transcription factors such as Osterix. Interestingly, downregulation of PP2A also stimulates adipocyte differentiation from undifferentiated mesenchymal cells under the appropriate adipogenic differentiation conditions. In osteoblasts, PP2A is also involved in the ability to control osteoclastogenesis as well as in the proliferation and metastasis of osteosarcoma cells. Thus, PP2A is considered to be a comprehensive factor in controlling the differentiation and function of cells derived from mesenchymal cells such as osteoblasts and adipocytes.

Peritoneal dialysis (PD) fluid, which contains a high concentration of glucose, is involved in peritoneal damage after long-term use. The mechanisms through which glucose induces damage to the mesothelium have not been clearly elucidated. Although, endoplasmic reticulum (ER) stress response is associated with several diseases, the involvement of ER stress in peritoneal damage has not yet been demonstrated. Primary-cultured rat peritoneal mesothelial cells (RPMCs) and rat PD model were used to investigate the influence of glucose on the peritoneum. Cells treated with glucose were examined for cytotoxicity, induction of apoptosis, and activation of the ER stress pathway. Glucose treatment of RPMCs induced cell death at concentrations higher than 3%. Annexin V positive, that is a feature of apoptosis, occurred in dead cells. Treatment with glucose led to the activation of protein kinase R-like ER kinase (PERK) and eukaryotic translation initiation factor-2α (eIF-2α). Glucose also induced the expression and nuclear translocation of homologous protein C/EBP. Cell death was rescued by the integrated stress response inhibitor, ISRIB, which suppresses the integrated stress response pathway, including ER stress. Glucose in PD fluid induces PERK/eIF-2α-mediated ER stress in RPMCs, resulting in apoptosis. This cellular stress may cause peritoneal damage in patients receiving PD.

Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the functional von Hippel–Lindau (VHL) complex and distinctive clear cell morphology associated with intracellular glycogen and lipid accumulation. However, the mechanism underlying glycogen storage remains unclear. This study was conducted to investigate the relationship between SGLT2, a glucose transporter predominantly expressed in proximal tubular epithelial cells; the cell of origin of ccRCC; and clear cell morphology in ccRCC. Using the VHL-null ccRCC cell line KMRC-1, we investigated the effects of the SGLT2 inhibitor dapagliflozin, SGLT2 knockdown, and VHL overexpression on cellular morphology, intracellular glycogen accumulation, and glucose uptake. Immunohistochemical expression of SGLT2, glucose transporter 1, and VHL was evaluated in morphologically heterogeneous ccRCC specimens. Periodic acid–Schiff (PAS) and PAS with diastase staining, together with quantitative image analysis of PAS-stained cells, showed that dapagliflozin treatment, SGLT2 knockdown, and VHL restoration reduced cytoplasmic area and cytoplasmic PAS staining intensity in KMRC-1 cells. In the fluorescent glucose uptake assay, dapagliflozin significantly reduced the fluorescence signal (p < 0.05). In paired intratumoral analyses of six VHL-deficient ccRCC specimens, SGLT2 immunohistochemical scores were significantly higher in clear cell components than in eosinophilic components (p = 0.026), whereas GLUT1 scores did not differ significantly (p = 0.850). These findings suggest that SGLT2-mediated glucose uptake contributes to glycogen accumulation and the glycogen-rich clear cell morphology of VHL-deficient ccRCC. The potential therapeutic relevance of SGLT2 inhibition in ccRCC warrants further investigation.