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Human Phosphatases
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Statistics

241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
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336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
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299 KEGG pathways;
876 Reactome pathways;
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last scientific update:
11 Mar, 2019
last maintenance update:
01 Sep, 2023

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EPM2A

Basic Information
Substrates
Pathway
Interacting Proteins
Phosphorylating Kinases

Gene Name	EPM2A (QuickGO)	Interactive visualization EPM2A structures (A quick tutorial to explore the interctive visulaization)
Synonyms	EPM2A
Protein Name	EPM2A
Alternative Name(s)	Laforin;3.1.3.-;3.1.3.16;3.1.3.48;Glucan phosphatase;Glycogen phosphatase;Lafora PTPase;LAFPTPase;
EntrezGene ID	7957 (Comparitive Toxicogenomics)
UniProt AC (Human)	O95278 (protein sequence)
Enzyme Class	EC 3.1.3.16 3.1.3.48 (BRENDA )
Molecular Weight	37158 Dalton
Protein Length	331 amino acids (AA)
Genome Browsers	NCBI \| ENSG00000112425 (Ensembl) \| UCSC
Crosslinking annotations	Query our ID-mapping table
Orthologues	Quest For Orthologues (QFO) \| GeneTree
Classification	Superfamily: Class I Cys-based PTPs --> Family: DSP \| Historic class: Class I Cys-based PTPs --> VH1-like or DSPs --> Atypical DSPs \| CATH ID: 3.90.190.10 \| SCOP Fold: CC1
Phosphatase activity	active \| Catalytic signature motif: HCNAGVGR
Phosphorylation Network	Visualize

Domain organization, Expression, Diseases

Localization, Function, Catalytic activity and Sequence

Localization (UniProt annotation)
Cytoplasm Note=Under glycogenolytic conditions localizes to the nucleus Isoform 1: Cytoplasm Endoplasmic reticulum membrane Cell membrane Note=Colocalizes with glycogensynthase in punctate structures in the cytoplasm (PubMed:11739371,PubMed:14532330) Primarily associated with polyribosomes at therough endoplasmic reticulum, and also detected at the plasmamembrane (PubMed:11001928, PubMed:11220751, PubMed:11883934,PubMed:18311786) Isoform 2: Cytoplasm Endoplasmic reticulum membrane Cell membrane Nucleus Note=Also found in the nucleus Isoform 4: Cytoplasm Nucleus Isoform 5: Cytoplasm Nucleus Isoform 7: Cytoplasm
Function (UniProt annotation)
Plays an important role in preventing glycogenhyperphosphorylation and the formation of insoluble aggregates,via its activity as glycogen phosphatase, and by promoting theubiquitination of proteins involved in glycogen metabolism via itsinteraction with the E3 ubiquitin ligase NHLRC1/malin Showsstrong phosphatase activity towards complex carbohydrates invitro, avoiding glycogen hyperphosphorylation which is associatedwith reduced branching and formation of insoluble aggregates(PubMed:16901901, PubMed:23922729, PubMed:26231210,PubMed:25538239, PubMed:25544560) Dephosphorylatesphosphotyrosine and synthetic substrates, such as para-nitrophenylphosphate (pNPP), and has low activity withphosphoserine and phosphothreonine substrates (in vitro)(PubMed:11001928, PubMed:11220751, PubMed:11739371,PubMed:14532330, PubMed:16971387, PubMed:18617530,PubMed:22036712, PubMed:23922729, PubMed:14722920) Has been shownto dephosphorylate MAPT (By similarity) Forms a complex withNHLRC1/malin and HSP70, which suppresses the cellular toxicity ofmisfolded proteins by promoting their degradation through theubiquitin-proteasome system (UPS) Acts as a scaffold protein tofacilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin(PubMed:23922729) Also promotes proteasome-independent proteindegradation through the macroautophagy pathway (PubMed:20453062) Isoform 2: does not bind to glycogen (PubMed:18617530)Lacks phosphatase activity and might function as a dominant-negative regulator for the phosphatase activity of isoform 1 andisoform 7 (PubMed:18617530, PubMed:22036712) Isoform 7: has phosphatase activity (in vitro)
Catalytic Activity (UniProt annotation)
Protein tyrosine phosphate + H(2)O = proteintyrosine + phosphate [a protein]-serine/threonine phosphate + H(2)O= [a protein]-serine/threonine + phosphate
Protein Sequence
MRFRFGVVVPPAVAGARPELLVVGSRPELGRWEPRGAVRLRPAGTAAGDGALALQEPGLWLGEVELAAEEAAQDGAEPGR VDTFWYKFLKREPGGELSWEGNGPHHDRCCTYNENNLVDGVYCLPIGHWIEATGHTNEMKHTTDFYFNIAGHQAMHYSRI LPNIWLGSCPRQVEHVTIKLKHELGITAVMNFQTEWDIVQNSSGCNRYPEPMTPDTMIKLYREEGLAYIWMPTPDMSTEG RVQMLPQAVCLLHALLEKGHIVYVHCNAGVGRSTAAVCGWLQYVMGWNLRKVQYFLMAKRPAVYIDEEALARAQEDFFQK FGKVRSSVCSL

Motif information from Eukaryotic Linear Motif atlas (ELM)

Gene Ontology (P: Process; F: Function and C: Component terms)

KEGG Pathway
Reactome Pathway

Pathway ID	Pathway Name	Pathway Description (KEGG)
R-HSA-3322077	Glycogen synthesis.	Glycogen, a highly branched glucose polymer, is formed and broken down in most human tissues, but is most abundant in liver and muscle, where it serves as a major stored fuel. Glycogen metabolism has been studied in most detail in muscle, although considerable experimental data are available concerning these reactions in liver as well. Glycogen metabolism in other tissues has not been studied as extensively, and is thought to resemble the muscle process. Glycogen synthesis involves five reactions. The first two, conversion of glucose 6-phosphate to glucose 1-phosphate and synthesis of UDP-glucose from glucose 1-phosphate and UTP, are shared with several other pathways. The next three reactions, the auto-catalyzed synthesis of a glucose oligomer on glycogenin, the linear extension of the glucose oligomer catalyzed by glycogen synthase, and the formation of branches catalyzed by glycogen branching enzyme, are unique to glycogen synthesis. Repetition of the last two reactions generates large, extensively branched glycogen polymers. The catalysis of glycogenin glucosylation and oligoglucose chain extension by distinct isozymes in liver and nonhepatic tissues allows them to be regulated independently (Agius 2008; Bollen et al. 1998; Roach et al. 2012)
R-HSA-3785653	Myoclonic epilepsy of Lafora.	Lafora disease is a progressive neurodegenerative disorder with onset typically late in childhood, characterized by seizures and progressive neurological deterioration and death within ten years of onset. Recessive mutations in EPM2A (laforin) and NHLRC1 (malin) have been identified as causes of the disease. The disease is classified here as one of glycogen storage as EPM2A (laforin) and NHLRC1 (malin) regulate normal glycogen turnover and defects in either protein are associated with the formation of Lafora bodies, accumulations of abnormal, insoluble glycogen molecules in tissues including brain, muscle, liver, and heart (Ramachandran et al. 2009; Roach et al. 2012). Consistent with a central role for glycogen accumulation in the disease, reduced (Turnbull et al. 2011) or absent (Pederson et al. 2013) glycogen synthase activity prevents Lafora Disease in mouse models. Type 2A disease. EPM2A (laforin) associated with cytosolic glycogen granules, normally catalyzes the removal of the phosphate groups added rarely but consistently to growing glycogen molecules (Tagliabracci et al. 2011). Defects in this catalytic activity lead to the formation of phosphorylated glycogen molecules that are insoluble and that show abnormal branching patterns (Minassian et al. 1998, Serratosa et al. 1999, Tagliabracci et al. 2011). Type 2B disease. NHLRC1 (malin) normally mediates polyubiquitination of EPM2A (laforin) and PPP1R3C (PTG). The two polyubiquitinated proteins are targeted for proteasome-mediated degradation, leaving a glycogen-glycogenin particle associated with glycogen synthase. In the absence of NHLRC1 activity, EPM2A and PPP1R3C proteins appear to persist, associated with the formation of abnormal, stable glycogen granules (Lafora bodies) (Chan et al. 2003; Gentry et al. 2005). In NHLRC1 knockout mice PPP1R3C levels are unchanged rather than increased, suggesting that NHLRC1 does not target PPP1R3C for degradation. However, EPM2A protein levels are increased in this knockout consistent with NHLRC1's proposed role (DePaoli-Roach et al. 2010)