Protein tyrosine phosphatases (PTPs) are a diverse group of enzymes that contain a highly conserved active site motif, Cys-x5-Arg (Cx5R). The PTP superfamily enzymes, which include tyrosine-specific, dual specificity, low-molecular-weight, and Cdc25 phosphatases, are key mediators of a wide variety of cellular processes, including growth, metabolism, differentiation, motility, and programmed cell death. The PTEN/MMAC1/TEP1 gene was originally identified as a candidate tumor suppressor gene located on human chromosome 10q23; it encodes a protein with sequence similarity to PTPs and tensin. Recent studies have demonstrated that PTEN plays an essential role in regulating signaling pathways involved in cell growth and apoptosis, and mutations in the PTEN gene are now known to cause tumorigenesis in a number of human tissues. In addition, germ line mutations in the PTEN gene also play a major role in the development of Cowden and Bannayan-Zonana syndromes, in which patients often suffer from increased risk of breast and thyroid cancers. Biochemical studies of the PTEN phosphatase have revealed a molecular mechanism by which tumorigenesis may be caused in individuals with PTEN mutations. Unlike most members of the PTP superfamily, PTEN utilizes the phosphoinositide second messenger, phosphatidylinositol 3,4,5-trisphosphate (PIP3), as its physiologic substrate. This inositol lipid is an important regulator of cell growth and survival signaling through the Ser/Thr protein kinases PDK1 and Akt. By specifically dephosphorylating the D3 position of PIP3, the PTEN tumor suppressor functions as a negative regulator of signaling processes downstream of this lipid second messenger. Mutations that impair PTEN function result in a marked increase in cellular levels of PIP3 and constitutive activation of Akt survival signaling pathways, leading to inhibition of apoptosis, hyperplasia, and tumor formation. Certain structural features of PTEN contribute to its specificity for PIP3, as well as its role(s) in regulating cellular proliferation and apoptosis. Recently, myotubularin, a second PTP superfamily enzyme associated with human disease, has also been shown to utilize a phosphoinositide as its physiologic substrate.

The lipid second messenger phosphatidylinositol 3-phosphate [PI(3)P] plays a crucial role in intracellular membrane trafficking. We report here that myotubularin, a protein tyrosine phosphatase required for muscle cell differentiation, is a potent PI(3)P phosphatase. Recombinant human myotubularin specifically dephosphorylates PI(3)P in vitro. Overexpression of a catalytically inactive substrate-trapping myotubularin mutant (C375S) in human 293 cells increases PI(3)P levels relative to that of cells overexpressing the wild-type enzyme, demonstrating that PI(3)P is a substrate for myotubularin in vivo. In addition, a Saccharomyces cerevisiae strain in which the myotubularin-like gene (YJR110w) is disrupted also exhibits increased PI(3)P levels. Both the recombinant yeast enzyme and a human myotubularin-related protein (KIAA0371) are able to dephosphorylate PI(3)P in vitro, suggesting that this activity is intrinsic to all myotubularin family members. Mutations in the MTM1 gene that cause human myotubular myopathy dramatically reduce the ability of the phosphatase to dephosphorylate PI(3)P. Our findings provide evidence that myotubularin exerts its effects during myogenesis by regulating cellular levels of the inositol lipid PI(3)P.X -linked myotubular myopathy is a severe congenital disorder in which the muscle cells of affected individuals contain large, centrally placed nuclei and structural features characteristic of fetal myotubes, suggesting that differentiation has been arrested at a step preceding myofiber formation (1-4). The myotubularin gene (MTM1), which is mutated in X-linked myotubular myopathy, encodes a protein with sequence similarity to dual specificity protein tyrosine phosphatases (5). Myotubularin contains the Cys-X 5 -Arg (CX 5 R) active site motif that is the hallmark of the protein tyrosine phosphatase (PTP) superfamily and exhibits dual specificity protein phosphatase activity in vitro (6-9). In addition, myotubularin-related proteins are conserved among eukaryotes, suggesting a common substrate or function (5, 9). However, the physiologic target(s) of myotubularin and its essential role in myogenic development have yet to be identified.Phosphoinositides produced by the actions of phosphatidylinositol (PI) 3-kinases play key roles in a diverse array of cellular processes, including responses to extracellular agonists, growth, survival, cytoskeletal organization, differentiation, and membrane trafficking (10)(11)(12)(13)(14). Recently, the PTEN͞MMAC1 gene was identified as a candidate tumor suppressor gene, which mapped to chromosome 10q23, a region frequently mutated in a variety of tumors (15, 16). The PTEN͞MMAC1 gene encodes a protein with similarity to dual specificity protein tyrosine phosphatases (15,16). Our laboratory has shown that PTEN (phosphatase and tensin homolog) dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PI (3,4,5)P 3 ), thus identifying it as the first PTP superfamily enzyme that utilizes an inositol lipid as its physiologic substr...

No abstract

This study examines the association between corporate social responsibility (CSR) performance and financial distress and additionally the moderating impact of firm life cycle stages on that association. Based on a sample of 651 publicly listed Australian firm‐years’ data covering the 2007–2013 period, our regression results show that positive CSR activity significantly reduces financial distress of the firm. In addition, the negative association between positive CSR performance and financial distress is more pronounced for firms in mature life cycle stages. Our results are robust to alternative proxy measures of financial distress, CSR performance and life cycle stages.

No abstract

Myotubularin is the archetype of a family of highly conserved protein-tyrosine phosphatase-like enzymes. The myotubularin gene, MTM1, is mutated in the genetic disorder, X-linked myotubular myopathy. We and others have previously shown that myotubularin utilizes the lipid second messenger, phosphatidylinositol 3-phosphate (PI(3)P), as a physiologic substrate. We demonstrate here that the myotubularin-related protein MTMR2, which is mutated in the neurodegenerative disorder, type 4B Charcot-Marie-Tooth disease, is also highly specific for PI(3)P as a substrate. Furthermore, the MTM-related phosphatases MTMR1, MTMR3, and MTMR6 also dephosphorylate PI(3)P, suggesting that activity toward this substrate is common to all myotubularin family enzymes. A direct comparison of the lipid phosphatase activities of recombinant myotubularin and MTMR2 demonstrates that their enzymatic properties are indistinguishable, indicating that the lack of functional redundancy between these proteins is likely to be due to factors other than the utilization of different physiologic substrates. To this end, we have analyzed myotubularin and MTMR2 transcripts during induced differentiation of cultured murine C2C12 myoblasts and find that their expression is divergently regulated. In addition, myotubularin and MTMR2 enhanced green fluorescent protein fusion proteins exhibit overlapping but distinct patterns of subcellular localization. Finally, we provide evidence that myotubularin, but not MTMR2, can modulate the levels of endosomal PI(3)P. From these data, we conclude that the developmental expression and subcellular localization of myotubularin and MTMR2 are differentially regulated, resulting in their utilization of specific cellular pools of PI(3)P. Myotubularin (MTM1)1 is a dual specificity protein-tyrosine phosphatase (PTP)-like enzyme that is mutated in X-linked myotubular myopathy, a severe congenital disorder in which muscle cell development is compromised (1-3). Myogenesis in affected individuals is arrested at a late stage of differentiation/ maturation following myotube formation, and the muscle cells have characteristic large centrally located nuclei (1). The MTM1 protein is the first characterized member of one of the largest families of dual specificity PTPs yet identified (reviewed in Refs. 4 and 5). The MTM family includes at least eight putative catalytically active proteins as well as four forms that are predicted to be enzymatically inactive (4 -7). The inactive MTM proteins contain substitutions at specific residues that are required for catalysis by PTP superfamily enzymes and may function as interaction modules (4 -8). Phylogenetic analysis of MTM family proteins indicates that they can be further divided into at least four distinct subgroups, which include the catalytically active MTM1/MTMR1/MTMR2, MTMR3/MTMR4, and MTMR6/MTMR7/MTMR8 enzymes, as well as the SBF1/LIP-STYX/MTMR10/3-PAP inactive forms (4 -7). Our laboratory and others have previously shown that myotubularin specifically dephosphorylates the D3 position ...

No abstract

No abstract