UniProt functional annotation for P67775



	UniProt functional annotation for P67775

UniProt code: P67775.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: PP2A is the major phosphatase for microtubule-associated proteins (MAPs). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGO2 to protect centromeric cohesin from separase- mediated cleavage in oocytes specifically during meiosis I (By similarity). Can dephosphorylate SV40 large T antigen and p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259' (PubMed:10801873). Mediates dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint (PubMed:33108758). {ECO:0000250, ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:22613722, ECO:0000269|PubMed:33108758, ECO:0000269|PubMed:9920888}.

Catalytic activity: Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] + phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474, ChEBI:CHEBI:83421; EC=3.1.3.16; Evidence={ECO:0000269|PubMed:1848668};

Catalytic activity: Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] + phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA- COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474, ChEBI:CHEBI:61977; EC=3.1.3.16; Evidence={ECO:0000269|PubMed:30595372, ECO:0000269|PubMed:30611118};

Cofactor: Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000269|PubMed:17055435}; Note=Binds 2 manganese ions per subunit. {ECO:0000269|PubMed:17055435};

Subunit: PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (PubMed:18394995, PubMed:30595372). Interacts with NXN; the interaction is direct (By similarity). Interacts with KCTD20 (By similarity). Interacts with BTBD10 (By similarity). Interacts with SGO1 and SGO2 (PubMed:16580887, PubMed:16541025, PubMed:17485487). Interacts with TP53 (PubMed:17245430). Interacts with AXIN1; the interaction dephosphorylates AXIN1. Interacts with PIM3; this interaction promotes dephosphorylation, ubiquitination and proteasomal degradation of PIM3. Interacts with RAF1. Interaction with IGBP1 protects unassembled PPP2CA from degradative ubiquitination. Interacts with GSK3B (via C2 domain). Interacts with MFHAS1; retains PPP2CA into the cytoplasm and excludes it from the nucleus (PubMed:28609714). Interacts with PABIR1/FAM122A (PubMed:27588481). Interacts with ADCY8; interaction is phosphatase activity-dependent; antagonizes interaction between ADCY8 and calmodulin (PubMed:16258073). Interacts with CRTC3 (when phosphorylated at 'Ser-391') (PubMed:30611118). Interacts with SPRY2; the interaction is inhibited by TESK1 interaction with SPRY2, possibly by vesicular sequestration of SPRY2 (PubMed:17974561). Interacts with TRAF3IP3 (PubMed:30115741). {ECO:0000250, ECO:0000250|UniProtKB:P63330, ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:12473674, ECO:0000269|PubMed:16258073, ECO:0000269|PubMed:16541025, ECO:0000269|PubMed:16580887, ECO:0000269|PubMed:17055435, ECO:0000269|PubMed:17245430, ECO:0000269|PubMed:17485487, ECO:0000269|PubMed:17974561, ECO:0000269|PubMed:18394995, ECO:0000269|PubMed:19818709, ECO:0000269|PubMed:20080667, ECO:0000269|PubMed:20092282, ECO:0000269|PubMed:27588481, ECO:0000269|PubMed:28609714, ECO:0000269|PubMed:30115741, ECO:0000269|PubMed:30595372, ECO:0000269|PubMed:30611118, ECO:0000269|PubMed:9647778, ECO:0000269|PubMed:9920888}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:16541025}. Nucleus {ECO:0000269|PubMed:16541025}. Chromosome, centromere {ECO:0000269|PubMed:16541025}. Cytoplasm, cytoskeleton, spindle pole {ECO:0000269|PubMed:16541025}. Note=In prometaphase cells, but not in anaphase cells, localizes at centromeres. During mitosis, also found at spindle poles. Centromeric localization requires the presence of SGO2 (By similarity). {ECO:0000250}.

Ptm: Reversibly methyl esterified on Leu-309 by leucine carboxyl methyltransferase 1 (LCMT1) and protein phosphatase methylesterase 1 (PPME1). Carboxyl methylation influences the affinity of the catalytic subunit for the different regulatory subunits, thereby modulating the PP2A holoenzyme's substrate specificity, enzyme activity and cellular localization. {ECO:0000269|PubMed:8206937}.

Ptm: Phosphorylation of either threonine (by autophosphorylation- activated protein kinase) or tyrosine results in inactivation of the phosphatase. Auto-dephosphorylation has been suggested as a mechanism for reactivation.

Ptm: Polyubiquitinated, leading to its degradation by the proteasome. {ECO:0000269|PubMed:27588481}.

Disease: Neurodevelopmental disorder and language delay with or without structural brain abnormalities (NEDLBA) [MIM:618354]: An autosomal dominant neurodevelopmental disorder characterized by global developmental delay with onset in infancy and additional variable features including hypotonia, epilepsy, brain abnormalities such as ventriculomegaly and a small corpus callosum, and autism spectrum disorder. {ECO:0000269|PubMed:30595372}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 2]: Catalytically inactive, shows enhanced binding to IGBP1, and does not interact with the scaffolding subunit PPP2R1A. {ECO:0000305}.

Similarity: Belongs to the PPP phosphatase family. PP-1 subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		PP2A is the major phosphatase for microtubule-associated proteins (MAPs). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGO2 to protect centromeric cohesin from separase- mediated cleavage in oocytes specifically during meiosis I (By similarity). Can dephosphorylate SV40 large T antigen and p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259' (PubMed:10801873). Mediates dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint (PubMed:33108758). {ECO:0000250, ECO:0000269\|PubMed:10801873, ECO:0000269\|PubMed:22613722, ECO:0000269\|PubMed:33108758, ECO:0000269\|PubMed:9920888}.


Catalytic activity:		Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] + phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474, ChEBI:CHEBI:83421; EC=3.1.3.16; Evidence={ECO:0000269\|PubMed:1848668};
Catalytic activity:		Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] + phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA- COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474, ChEBI:CHEBI:61977; EC=3.1.3.16; Evidence={ECO:0000269\|PubMed:30595372, ECO:0000269\|PubMed:30611118};
Cofactor:		Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000269\|PubMed:17055435}; Note=Binds 2 manganese ions per subunit. {ECO:0000269\|PubMed:17055435};
Subunit:		PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (PubMed:18394995, PubMed:30595372). Interacts with NXN; the interaction is direct (By similarity). Interacts with KCTD20 (By similarity). Interacts with BTBD10 (By similarity). Interacts with SGO1 and SGO2 (PubMed:16580887, PubMed:16541025, PubMed:17485487). Interacts with TP53 (PubMed:17245430). Interacts with AXIN1; the interaction dephosphorylates AXIN1. Interacts with PIM3; this interaction promotes dephosphorylation, ubiquitination and proteasomal degradation of PIM3. Interacts with RAF1. Interaction with IGBP1 protects unassembled PPP2CA from degradative ubiquitination. Interacts with GSK3B (via C2 domain). Interacts with MFHAS1; retains PPP2CA into the cytoplasm and excludes it from the nucleus (PubMed:28609714). Interacts with PABIR1/FAM122A (PubMed:27588481). Interacts with ADCY8; interaction is phosphatase activity-dependent; antagonizes interaction between ADCY8 and calmodulin (PubMed:16258073). Interacts with CRTC3 (when phosphorylated at 'Ser-391') (PubMed:30611118). Interacts with SPRY2; the interaction is inhibited by TESK1 interaction with SPRY2, possibly by vesicular sequestration of SPRY2 (PubMed:17974561). Interacts with TRAF3IP3 (PubMed:30115741). {ECO:0000250, ECO:0000250\|UniProtKB:P63330, ECO:0000269\|PubMed:10801873, ECO:0000269\|PubMed:12473674, ECO:0000269\|PubMed:16258073, ECO:0000269\|PubMed:16541025, ECO:0000269\|PubMed:16580887, ECO:0000269\|PubMed:17055435, ECO:0000269\|PubMed:17245430, ECO:0000269\|PubMed:17485487, ECO:0000269\|PubMed:17974561, ECO:0000269\|PubMed:18394995, ECO:0000269\|PubMed:19818709, ECO:0000269\|PubMed:20080667, ECO:0000269\|PubMed:20092282, ECO:0000269\|PubMed:27588481, ECO:0000269\|PubMed:28609714, ECO:0000269\|PubMed:30115741, ECO:0000269\|PubMed:30595372, ECO:0000269\|PubMed:30611118, ECO:0000269\|PubMed:9647778, ECO:0000269\|PubMed:9920888}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:16541025}. Nucleus {ECO:0000269\|PubMed:16541025}. Chromosome, centromere {ECO:0000269\|PubMed:16541025}. Cytoplasm, cytoskeleton, spindle pole {ECO:0000269\|PubMed:16541025}. Note=In prometaphase cells, but not in anaphase cells, localizes at centromeres. During mitosis, also found at spindle poles. Centromeric localization requires the presence of SGO2 (By similarity). {ECO:0000250}.
Ptm:		Reversibly methyl esterified on Leu-309 by leucine carboxyl methyltransferase 1 (LCMT1) and protein phosphatase methylesterase 1 (PPME1). Carboxyl methylation influences the affinity of the catalytic subunit for the different regulatory subunits, thereby modulating the PP2A holoenzyme's substrate specificity, enzyme activity and cellular localization. {ECO:0000269\|PubMed:8206937}.
Ptm:		Phosphorylation of either threonine (by autophosphorylation- activated protein kinase) or tyrosine results in inactivation of the phosphatase. Auto-dephosphorylation has been suggested as a mechanism for reactivation.
Ptm:		Polyubiquitinated, leading to its degradation by the proteasome. {ECO:0000269\|PubMed:27588481}.
Disease:		Neurodevelopmental disorder and language delay with or without structural brain abnormalities (NEDLBA) [MIM:618354]: An autosomal dominant neurodevelopmental disorder characterized by global developmental delay with onset in infancy and additional variable features including hypotonia, epilepsy, brain abnormalities such as ventriculomegaly and a small corpus callosum, and autism spectrum disorder. {ECO:0000269\|PubMed:30595372}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 2]: Catalytically inactive, shows enhanced binding to IGBP1, and does not interact with the scaffolding subunit PPP2R1A. {ECO:0000305}.
Similarity:		Belongs to the PPP phosphatase family. PP-1 subfamily. {ECO:0000305}.