Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains

Wishart, Matthew J.; Dixon, Jack E.

doi:10.1016/s0968-0004(98)01241-9

Cited by 129 publications

(154 citation statements)

References 46 publications

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“…These studies suggested a model in which neoplastic transformation induced by Sbf1 (or the SID) resulted from antagonism of endogenous phosphatases and consequent impaired dephosphorylation of critical subordinate proteins. Sbf1 and STYX are the only proteins identified to date that contain naturally occurring inactivating mutations in their catalytic pockets that abrogate their capacity to function as phosphatases (55). Their ability to bind but not dephosphorylate synthetic phosphopeptides suggests that they may function as protective factors to prevent dephosphorylation of substrates (21).…”

Section: Discussionmentioning

confidence: 99%

“…Sbf1 is similar to dual-specificity phosphatases of the myotubularin family but lacks several crucial residues in the catalytic pocket which render it catalytically inactive as a phos-phatase. The pocket is sufficiently preserved, however, to bind phosphorylated synthetic substrates (9), suggesting a possible role as a protective factor that competes with functional phosphatases for substrate interaction (55). Mutated forms of Sbf1 are highly oncogenic, and a conserved motif in Sbf1 that mediates interactions with SET domains in vitro is necessary and sufficient for oncogenic activity (9,10).…”

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confidence: 99%

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Set Domain-Dependent Regulation of Transcriptional Silencing and Growth Control by SUV39H1, a Mammalian Ortholog of Drosophila Su(var)3-9

Firestein

Cui

Huie

et al. 2000

Molecular and Cellular Biology

101

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Mammalian SET domain-containing proteins define a distinctive class of chromatin-associated factors that are targets for growth control signals and oncogenic activation. SUV39H1, a mammalian ortholog of Drosophila Su(var)3-9, contains both SET and chromo domains, signature motifs for proteins that contribute to epigenetic control of gene expression through effects on the regional organization of chromatin structure. In this report we demonstrate that SUV39H1 represses transcription in a transient transcriptional assay when tethered to DNA through the GAL4 DNA binding domain. Under these conditions, SUV39H1 displays features of a long-range repressor capable of acting over several kilobases to silence basal promoters. A possible role in chromatin-mediated gene silencing is supported by the localization of exogenously expressed SUV39H1 to nuclear bodies with morphologic features suggestive of heterochromatin in interphase cells. In addition, we show that SUV39H1 is phosphorylated specifically at the G 1 /S cell cycle transition and when forcibly expressed suppresses cell growth. Growth suppression as well as the ability of SUV39H1 to form nuclear bodies and silence transcription are antagonized by the oncogenic antiphosphatase Sbf1 that when hyperexpressed interacts with the SET domain and stabilizes the phosphorylated form of SUV39H1. These studies suggest a phosphorylation-dependent mechanism for regulating the chromatin organizing activity of a mammalian su(var) protein and implicate the SET domain as a gatekeeper motif that integrates upstream signaling pathways to epigenetic regulation and growth control.The formation and propagation of higher-order chromatin states are dynamic processes that establish distinct domains that are either permissive or restrictive for transcription. The functions of such domains have been implicated in the epigenetic control of developmental gene expression in Drosophila (38), proper sister chromatid segregation during meiosis (11), and telomeric and centromeric silencing in yeast (22,35). The molecular mechanisms that regulate these and other properties of higher-order chromatin are essentially unknown.Genetic analyses in Drosophila and yeast have identified several genes that participate in the formation of euchromatin or heterochromatin states. Some of these encode proteins that contribute to either an enhancement [E(var)] or suppression [Su(var)] of position effect variegation (PEV) (42). PEV is a gene silencing mechanism that results from the spreading of heterochromatin, thus implicating E(var) and Su(var) proteins in the formation of euchromatic and heterochromatic domains, respectively. Several E(var) and Su(var) proteins share distinctive motifs that are important for their ability to organize chromatin domains. The Su(var)3-9 protein and its mammalian ortholog SUV39H1 are unique in being the only characterized PEV modifiers that share two of these consensus motifs, the chromo and SET domains (1, 50). Chromo domains are 40-amino-acid modular motifs that are implicated in...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Set Domain-Dependent Regulation of Transcriptional Silencing and Growth Control by SUV39H1, a Mammalian Ortholog of Drosophila Su(var)3-9

Firestein

Cui

Huie

et al. 2000

Molecular and Cellular Biology

101

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“…A potential role in substrate trapping or docking has been proposed (25,27), but the exact role of the inactive phosphatase members is still unknown. This study signifies that differential binding partners may be a mechanism to assign different biological roles to MTM1 and MTMR2.…”

Section: Mtmr2 Localization Is Regulated Through Its Interaction Withmentioning

confidence: 99%

“…Although the exact role of MTMR inactive forms is still unclear, previous reports suggest that the ''dead'' phosphatases may function either as interaction modules or as naturally occurring substrate-trapping mutants (25)(26)(27). The most extensively characterized catalytically inactive MTMR protein is MTMR5.…”

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confidence: 99%

Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase

Kim

Vacratsis

Firestein

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

126

133

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The myotubularin (MTM) family constitutes one of the most highly conserved protein-tyrosine phosphatase subfamilies in eukaryotes. MTM1, the archetypal member of this family, is mutated in X-linked myotubular myopathy, whereas mutations in the MTMrelated (MTMR)2 gene cause the type 4B1 Charcot-Marie-Tooth disease, a severe hereditary motor and sensory neuropathy. In this study, we identified a protein that specifically interacts with MTMR2 but not MTM1. The interacting protein was shown by mass spectrometry to be MTMR5, a catalytically inactive member of the MTM family. We also demonstrate that MTMR2 interacts with MTMR5 via its coiled-coil domain and that mutations in the coiledcoil domain of either MTMR2 or MTMR5 abrogate this interaction. Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization. This article demonstrates an active MTM member being regulated by an inactive family member.T he myotubularin (MTM) family constitutes one of the largest and most highly conserved protein-tyrosine phosphatase (PTP) subfamilies in eukaryotes (1-3). The human MTM family of phosphatases includes MTM1͞MTM-related (MTMR)1͞ MTMR2, MTMR3͞MTMR4, and MTMR6͞MTMR7͞MTMR8 subgroups (1, 3). The consensus CX 5 R active site motif is found in the MTM family and the sequence "CSDGWDR" is invariant within all of the enzymatically active members of this family. Most PTPs use phosphoproteins as substrates and specifically dephosphorylate substrates containing only phosphotyrosine sites. Other phosphatases, collectively known as dual-specificity phosphatases, are capable of removing phosphoserines͞ threonines and phosphotyrosines from protein substrates.Initially, MTM1 was reported to be a dual-specificity phosphatase (4-6). However, we and others have demonstrated that MTM1 utilizes the lipid second messenger, phosphatidylinositol 3-phosphate [PI(3)P], as a physiological substrate (7,8). Recent findings demonstrate that other MTMR phosphatases MTMR1, MTMR2, MTMR3, MTMR4, and MTMR6 also dephosphorylate PI(3)P, suggesting that activity toward this substrate is common to all active MTM family members (9-12). MTMR2 and MTMR3 have also been shown to dephosphorylate phosphatidylinositol 3,5-bisphosphate (9, 13). PI(3)P plays a key role in membrane trafficking͞vesicular transport processes and serves as a targeting mechanism for proteins containing specific PI(3)P-binding modules such as Fab1͞YOTB͞Vac1p͞EEA1 (FYVE), pleckstrin homology (PH), and Phox homology domains (14-17).To date, two MTMR proteins have been associated with human diseases. The MTM1 gene on chromosome Xq28 is mutated in X-linked myotubular myopathy, a severe congenital muscular disorder characterized by hypotonia and generalized muscle weakness in newborn males (18,19 MTM1 and MTMR2 are highly similar proteins (64% identity, 76% similarity), use the same physiologic substrate, and have a ubiquitous expression pattern (6, 9-12). However, mutations in MTM1 and MTMR2 cause different diseases with different target tissues...

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“…E-mail address: hmdosch@sickkids.on.ca. © 2000 by The American Society for Cell Biology 3277 broad neuroendocrine expression pattern and that has been suggested to regulate vesicle trafficking in conjunction with the related protein phogrin (Solimena et al, 1996;Wasmeier and Hutton, 1996;Wishart and Dixon, 1998). ICA69 (islet cell autoantigen of 69 kDa) is a novel protein that is also a common target of diabetic autoimmunity in humans and diabetes-prone rodents (Pietropaolo et al, 1993;Miyazaki et al, 1994Miyazaki et al, , 1995Martin et al, 1995;Roep et al, 1996;Karges et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

The Diabetes Autoantigen ICA69 and ItsCaenorhabditis elegansHomologue,ric-19, Are Conserved Regulators of Neuroendocrine Secretion

Pilon

Peng

Spence

et al. 2000

MBoC

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ICA69 is a diabetes autoantigen with no homologue of known function. Given that most diabetes autoantigens are associated with neuroendocrine secretory vesicles, we sought to determine if this is also the case for ICA69 and whether this protein participates in the process of neuroendocrine secretion. Western blot analysis of ICA69 tissue distribution in the mouse revealed a correlation between expression levels and secretory activity, with the highest expression levels in brain, pancreas, and stomach mucosa. Subcellular fractionation of mouse brain revealed that although most of the ICA69 pool is cytosolic and soluble, a subpopulation is membrane-bound and coenriched with synaptic vesicles. We used immunostaining in the HIT insulin-secreting ␤-cell line to show that ICA69 localizes in a punctate manner distinct from the insulin granules, suggesting an association with the synaptic-like microvesicles found in these cells. To pursue functional studies on ICA69, we chose to use the model organism Caenorhabditis elegans, for which a homologue of ICA69 exists. We show that the promoter of the C. elegans ICA69 homologue is specifically expressed in all neurons and specialized secretory cells. A deletion mutant was isolated and found to exhibit resistance to the drug aldicarb (an inhibitor of acetylcholinesterase), suggesting defective neurotransmitter secretion in the mutant. On the basis of the aldicarb resistance phenotype, we named the gene ric-19 (resistance to inhibitors of cholinesterase-19). The resistance to aldicarb was rescued by introducing a ric-19 transgene into the ric-19 mutant background. This is the first study aimed at dissecting ICA69 function, and our results are consistent with the interpretation that ICA69/RIC-19 is an evolutionarily conserved cytosolic protein participating in the process of neuroendocrine secretion via association with certain secretory vesicles. INTRODUCTIONTwo main types of specialized secretory vesicles are found in insulin-secreting ␤-cells: dense-core insulin secretory vesicles, which contain a cargo of semicrystalized insulin granules, and lighter synaptic-like microvesicles (SLMVs), which carry a cargo of neurotransmitters such as ␥-aminobutyric acid. Type I diabetes results from the autoimmune destruction of pancreatic ␤-cells, and most of the known protein targets of the diabetogenic autoimmune attack have in common that they are components of the secretory vesicles found in ␤-cells. Autoantigens include proinsulin (Palmer et al., 1983), carboxypeptidase H (Castano et al., 1991, glutamate decarboxylase (GAD) (Baekkeskov et al., 1990), 38-kDa protein (Roep et al., 1990), IA-2/ICA512 (Lan et al., 1994;Rabin et al., 1994;Solimena et al., 1996) and its related protein phogrin (Hawkes et al., 1996), the Glima-38 antigen (Aanstoot et al., 1996), and the GM2-1 ganglioside (Dotta et al., 1998). Although diabetes is primarily a ␤-cell-specific autoimmune disease, expression of the autoantigens is usually not restricted to this cell type but rather exhibits much broader neuroend...

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Gathering STYX: phosphatase-like form predicts functions for unique protein-interaction domains

Cited by 129 publications

References 46 publications

Set Domain-Dependent Regulation of Transcriptional Silencing and Growth Control by SUV39H1, a Mammalian Ortholog of Drosophila Su(var)3-9

Set Domain-Dependent Regulation of Transcriptional Silencing and Growth Control by SUV39H1, a Mammalian Ortholog of Drosophila Su(var)3-9

Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase

The Diabetes Autoantigen ICA69 and ItsCaenorhabditis elegansHomologue,ric-19, Are Conserved Regulators of Neuroendocrine Secretion

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