Serine/threonine protein phosphatase 5 regulates glucose homeostasis in vivo and apoptosis signalling in mouse pancreatic islets and clonal MIN6 cells

Abstract

Aims/hypothesis During the development of type 2 diabetes mellitus, beta cells are often exposed to a high glucose/ hyperlipidaemic environment, in which the levels of reactive oxygen species (ROS) are elevated. In turn, ROS can trigger an apoptotic response leading to beta cell death, by activating mitogen-activated protein kinase (MAPK) signalling cascades. Here we test the hypothesis that serine/threonine protein phosphatase 5 (PP5) acts to suppress proapoptotic c-Jun N-terminal kinase (JNK) signalling in beta cells. Methods Ppp5c−/− and Ppp5c +/+ mice were subjected to intraperitoneal glucose (IPGTT)

Protein phosphatases in pancreatic islets

“…PP5 may accordingly act as a negative regulator of the ASK1/JNK signaling pathway and in so doing protecting cells from apoptosis (Kutuzov et al 2005; Mkaddem, et al 2009; Morita et al 2001). This concept was supported by the recent publication (Grankvist et al 2012) showing that islets from mice lacking PP5 were more susceptible towards stress-induced apoptosis than wild-type cognates. Additionally, PP5-deficient mice had lower fasting glycemia and improved glucose tolerance compared to the wild-type mice, suggesting a novel role for PP5 in the regulation of glucose homeostasis.…”

“…Additionally, PP5-deficient mice had lower fasting glycemia and improved glucose tolerance compared to the wild-type mice, suggesting a novel role for PP5 in the regulation of glucose homeostasis. These findings cannot be explained by a difference in islet mass between the PP5-deficient and wild-type mice, since no difference was observed (Grankvist et al 2012). Furthermore, a high-fat diet treatment for 10 weeks revealed that the mice lacking PP5 gained markedly less weight, did not accumulate visceral fat and displayed enhanced insulin sensitivity compared to the wild-type littermates (Grankvist et al 2013).…”

“…PP5 was recently shown for the first time to play a role in the β-cells (Grankvist et al 2012). During the progression towards T2D, β-cells are often exposed to a combination of high levels of glucose and fatty acids, producing so-called glucolipotoxicity, which is associated with increased production of reactive oxygen species (ROS) (Oprescu, et al 2007).…”

Proteomic Analysis of the Effect of Acupuncture on the Suppression of Kainic Acid-Induced Neuronal Destruction in Mouse Hippocampus

“…The decrease of PURA reduces postsynaptic density protein 95 [22], which contributes to neuronal cell loss after status epilepticus [23] and KA administration [24]. PP5, a serine/threonine phosphatase, is widely expressed in brain including hippocampus [25] and suppresses apoptosis by regulating c-Jun N-terminal kinase phosphorylation [26] and apoptosis signal-regulating kinase 1 activity [27]. T-complex protein 1 (TCP-1), a chaperonin family member, that folds protein properly [28], supports the maintenance of the native forms of cytoskeletal proteins [29], and the overexpression of all TCP-1 subunits suppressed Neuro2a cell death induced by the cytotoxicity of polyglutamine-expansion proteins [30].…”

Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor‐β pathway

“…It could be that other SMAD2/3 interacting partners could be dephosphorylated by PP5. Thirdly, PP5 has been implicated in the regulation of multiple pathways, including adipogenesis by controlling the GRα and PPARγ phosphorylation (34), DNA-damage repair by controlling the ATM/ATR/Chk1 and p53 pathway components (21,31,34-37), MAPK-mediated growth and differentiation (38)(39)(40)(41)(42)(43)(44), and cell cycle arrest (45). Interestingly, GRα has also been implicated in the repression of the TGFβ pathway by its association with SMAD3 (46).…”