UniProt functional annotation for Q9Y2R2



	UniProt functional annotation for Q9Y2R2

UniProt code: Q9Y2R2.

Organism: Homo sapiens (Human).

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

Function: Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules (PubMed:16461343, PubMed:18056643). Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue (PubMed:21719704). Dephosphorylates ZAP70 at its activating 'Tyr-493' residue (PubMed:16461343). Dephosphorylates the immune system activator SKAP2 (PubMed:21719704). Positively regulates toll-like receptor (TLR)-induced type 1 interferon production (PubMed:23871208). Promotes host antiviral responses mediated by type 1 interferon (By similarity). Regulates NOD2-induced pro-inflammatory cytokine secretion and autophagy (PubMed:23991106). Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide (also called N-arachidonoylethanolamide) (By similarity). {ECO:0000250|UniProtKB:P29352, ECO:0000269|PubMed:16461343, ECO:0000269|PubMed:18056643, ECO:0000269|PubMed:19167335, ECO:0000269|PubMed:21719704, ECO:0000269|PubMed:23871208, ECO:0000269|PubMed:23991106}.

Catalytic activity: Reaction=H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] + phosphate; Xref=Rhea:RHEA:10684, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620; EC=3.1.3.48; Evidence={ECO:0000255|PROSITE- ProRule:PRU10044, ECO:0000269|PubMed:21719704};

Catalytic activity: Reaction=H2O + N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine phosphate = N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine + phosphate; Xref=Rhea:RHEA:56532, ChEBI:CHEBI:2700, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:131894; Evidence={ECO:0000250|UniProtKB:P29352}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:56533; Evidence={ECO:0000250|UniProtKB:P29352};

Activity regulation: Down-regulated by phosphorylation.

Subunit: Interacts with CSK (PubMed:15208781). Interacts with LPXN (By similarity). Interacts with CBL (PubMed:10068674). Interacts with TRAF3 (via MATH domain); the interaction promotes TRAF3 polyubiquitination (PubMed:23871208). {ECO:0000250|UniProtKB:P29352, ECO:0000269|PubMed:10068674, ECO:0000269|PubMed:15208781, ECO:0000269|PubMed:18056643, ECO:0000269|PubMed:21719704, ECO:0000269|PubMed:23871208, ECO:0000269|Ref.19}.

Subcellular location: Cytoplasm {ECO:0000250|UniProtKB:P29352}.

Tissue specificity: Expressed in bone marrow, B and T-cells, PBMCs, natural killer cells, monocytes, dendritic cells and neutrophils (PubMed:15208781). Both isoform 1 and 4 are predominantly expressed in lymphoid tissues and cells. Isoform 1 is expressed in thymocytes and both mature B and T-cells. {ECO:0000269|PubMed:15208781}.

Induction: By muramyl-dipeptide and lipopolysaccharide. {ECO:0000269|PubMed:23991106}.

Ptm: Phosphorylation on Ser-35 by PKC/PRKCD abrogates its ability to dephosphorylate and inactivate the SRC family kinases. {ECO:0000269|PubMed:18056643}.

Disease: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:15273934}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Disease: Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15004560}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Disease: Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. {ECO:0000269|PubMed:15208781}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Disease: Vitiligo (VTLG) [MIM:193200]: A pigmentary disorder of the skin and mucous membranes. It is characterized by circumscribed depigmented macules and patches, commonly on extensor aspects of extremities, on the face or neck and in skin folds. Vitiligo is a progressive disorder in which some or all of the melanocytes in the affected skin are selectively destroyed. It is a multifactorial disorder with a complex etiology probably including autoimmune mechanisms, and is associated with an elevated risk of other autoimmune diseases. {ECO:0000269|PubMed:16015369}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 2]: Due to intron retention. {ECO:0000305}.

Miscellaneous: [Isoform 6]: Lacks most of the phosphatase domain and functions as a dominant negative isoform of the full length PTPN22. {ECO:0000305}.

Similarity: Belongs to the protein-tyrosine phosphatase family. Non- receptor class 4 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:		Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules (PubMed:16461343, PubMed:18056643). Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue (PubMed:21719704). Dephosphorylates ZAP70 at its activating 'Tyr-493' residue (PubMed:16461343). Dephosphorylates the immune system activator SKAP2 (PubMed:21719704). Positively regulates toll-like receptor (TLR)-induced type 1 interferon production (PubMed:23871208). Promotes host antiviral responses mediated by type 1 interferon (By similarity). Regulates NOD2-induced pro-inflammatory cytokine secretion and autophagy (PubMed:23991106). Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide (also called N-arachidonoylethanolamide) (By similarity). {ECO:0000250\|UniProtKB:P29352, ECO:0000269\|PubMed:16461343, ECO:0000269\|PubMed:18056643, ECO:0000269\|PubMed:19167335, ECO:0000269\|PubMed:21719704, ECO:0000269\|PubMed:23871208, ECO:0000269\|PubMed:23991106}.


Catalytic activity:		Reaction=H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] + phosphate; Xref=Rhea:RHEA:10684, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620; EC=3.1.3.48; Evidence={ECO:0000255\|PROSITE- ProRule:PRU10044, ECO:0000269\|PubMed:21719704};
Catalytic activity:		Reaction=H2O + N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine phosphate = N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine + phosphate; Xref=Rhea:RHEA:56532, ChEBI:CHEBI:2700, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:131894; Evidence={ECO:0000250\|UniProtKB:P29352}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:56533; Evidence={ECO:0000250\|UniProtKB:P29352};
Activity regulation:		Down-regulated by phosphorylation.
Subunit:		Interacts with CSK (PubMed:15208781). Interacts with LPXN (By similarity). Interacts with CBL (PubMed:10068674). Interacts with TRAF3 (via MATH domain); the interaction promotes TRAF3 polyubiquitination (PubMed:23871208). {ECO:0000250\|UniProtKB:P29352, ECO:0000269\|PubMed:10068674, ECO:0000269\|PubMed:15208781, ECO:0000269\|PubMed:18056643, ECO:0000269\|PubMed:21719704, ECO:0000269\|PubMed:23871208, ECO:0000269\|Ref.19}.
Subcellular location:		Cytoplasm {ECO:0000250\|UniProtKB:P29352}.
Tissue specificity:		Expressed in bone marrow, B and T-cells, PBMCs, natural killer cells, monocytes, dendritic cells and neutrophils (PubMed:15208781). Both isoform 1 and 4 are predominantly expressed in lymphoid tissues and cells. Isoform 1 is expressed in thymocytes and both mature B and T-cells. {ECO:0000269\|PubMed:15208781}.
Induction:		By muramyl-dipeptide and lipopolysaccharide. {ECO:0000269\|PubMed:23991106}.
Ptm:		Phosphorylation on Ser-35 by PKC/PRKCD abrogates its ability to dephosphorylate and inactivate the SRC family kinases. {ECO:0000269\|PubMed:18056643}.
Disease:		Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269\|PubMed:15273934}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Disease:		Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269\|PubMed:15004560}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Disease:		Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. {ECO:0000269\|PubMed:15208781}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Disease:		Vitiligo (VTLG) [MIM:193200]: A pigmentary disorder of the skin and mucous membranes. It is characterized by circumscribed depigmented macules and patches, commonly on extensor aspects of extremities, on the face or neck and in skin folds. Vitiligo is a progressive disorder in which some or all of the melanocytes in the affected skin are selectively destroyed. It is a multifactorial disorder with a complex etiology probably including autoimmune mechanisms, and is associated with an elevated risk of other autoimmune diseases. {ECO:0000269\|PubMed:16015369}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 2]: Due to intron retention. {ECO:0000305}.
Miscellaneous:		[Isoform 6]: Lacks most of the phosphatase domain and functions as a dominant negative isoform of the full length PTPN22. {ECO:0000305}.
Similarity:		Belongs to the protein-tyrosine phosphatase family. Non- receptor class 4 subfamily. {ECO:0000305}.