PP2C family members play key roles in regulation of cell survival and apoptosis

Abstract

U nlimited proliferation is typical of cancer cells, a phenotype supported by several distinct biological events, including enhanced cell proliferation, increased cell survival, and decreased cell death. Studies examining the molecular bases of these events have identified a variety of signaling pathways that are involved in their regulation. The mechanisms by which these different signaling pathways are coordinated to regulate proliferation and survival of cancer cells has remained poorly understood.ROS are normally generated by mitochondria during respiration, but can also be generated by inducible enzyme systems in mammalian cells.(1) Cellular ROS levels increase following exposure to a variety of stress agents, such as anticancer drugs.(2) Upregulation of these highly reactive molecules promotes apoptosis by stimulating the activation of pro-apoptotic signaling molecules, such as JNK and p38 (Fig. 1). (3,4) ROS also function in p53-induced apoptosis. In contrast, low levels of ROS stimulate normal cell proliferation under non-stress conditions; ROS production was reported to be increased in cancer cells (6,7) (Fig. 1). Elevated ROS appear to maintain the constitutive activation of transcription factors (NF-κB and AP-1) during tumor progression.(8) Overexpression of Mox1, the catalytic subunit of NADPH oxidase, induces superoxide generation, leading to the transformation of NIH 3T3 cells.(9) Thus, ROS might play a critical role in the pathogenesis of cancer. The diverse, and even opposing, effects of ROS on cell behavior reflect the complex nature of the biological functions of these highly reactive molecules.Integrins, a large family of adhesion receptors including more than 20 members, mediate highly dynamic cell-cell and cellextracellular matrix interactions. Integrin-mediated cell adhesion regulates a wide variety of biological processes, including cell migration, survival, and proliferation. The association and dissociation of integrin and their ligands are achieved by changes in the conformations of integrin molecules. Adoption of the active conformation triggered by intracellular signaling and cytoskeletal assembly, resulting in ligand binding, integrin clustering, and recruitment of cytoplasmic plaque proteins to integrin attachment sites, called focal adhesions.(10,11) ILK plays a central role in integrin activation and signaling.(12) ILK is composed of three structurally distinct domains, three ankyrin repeats near the N-terminus, a short linker sequence, and a Cterminal kinase domain.Functional studies of ILK1 revealed that GSK3β is a target of ILK1.(13) GSK3β, an important mediator of developmental signaling through the Wnt/wingless pathway, alters the transcriptional activity of Tcf/Lef factors through phosphorylation of the transcriptional cofactor β-catenin.(14,15) GSK3β-mediated phosphorylation targets β-catenin for degradation. Overexpression of ILK1 in epithelial cells induces the phosphorylation of GSK3β at Ser9, an inhibitory modification that results in the stabilization and nuclear trans...

Cell cycle-dependent Cdc25C phosphatase determines cell survival by regulating apoptosis signal-regulating kinase 1

“…31 Several phosphatases that dephosphorylate some of these sites have been identified. Serine/threonine protein phosphatase type 5 (PP5) and PP2C dephosphorylate phosphorylated (p)-Thr-838, 28,32 whereas PP2A and SHP2 dephosphorylate p-Ser-967 and p-Tyr-718, respectively. 31,33 Little is known about the kinase or phosphatase that regulates phosphorylation at Ser-1034.…”

Protein Phosphatase-1 Inhibitor-3 Is an in Vivo Target of Caspase-3 and Participates in the Apoptotic Response

“…BAD phosphorylation is maintained by growth factor signaling, and withdrawal of growth factors leads to dephosphorylation of BAD and the activation of the intrinsic mitochondrial pathway (28,34). Several protein phosphatases have been implicated in BAD dephosphorylation, including PP1␣ (35-37), PP2A (38), PP2B (39), and PP2C (40). Caspase-9 activation also has been reported to be dependent on PP1␣ activity (41).…”

Deeper Insights into Hematological Oncology Disorders via Single-Cell Phospho-Signaling Analysis

“…[4][5][6] Phosphorylation occurs rapidly, controls almost all cellular processes, and is sufficiently stable and distinct as a chemical entity that antibody reagents can be developed to recognize the presence or absence of phosphorylation on proteins or lipids. Using antibodies against phosphorylated proteins researchers have mapped numerous cell-signaling pathologies related to cancer, as well as demonstrated the molecular entities and mutations driving their function.…”