UniProt functional annotation for P25911



	UniProt functional annotation for P25911

UniProt code: P25911.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-96'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (PubMed:28098138). Phosphorylates CLNK (PubMed:12681493). {ECO:0000250|UniProtKB:P07948, ECO:0000269|PubMed:10327049, ECO:0000269|PubMed:10594694, ECO:0000269|PubMed:10640270, ECO:0000269|PubMed:10672044, ECO:0000269|PubMed:11007759, ECO:0000269|PubMed:11435302, ECO:0000269|PubMed:11672542, ECO:0000269|PubMed:12077122, ECO:0000269|PubMed:12681493, ECO:0000269|PubMed:12874221, ECO:0000269|PubMed:14525964, ECO:0000269|PubMed:14726379, ECO:0000269|PubMed:15335855, ECO:0000269|PubMed:16034130, ECO:0000269|PubMed:16116174, ECO:0000269|PubMed:16249387, ECO:0000269|PubMed:16272347, ECO:0000269|PubMed:16731527, ECO:0000269|PubMed:17640867, ECO:0000269|PubMed:19492092, ECO:0000269|PubMed:20189992, ECO:0000269|PubMed:20385881, ECO:0000269|PubMed:28098138, ECO:0000269|PubMed:7513017, ECO:0000269|PubMed:7584145, ECO:0000269|PubMed:7585947, ECO:0000269|PubMed:8128248, ECO:0000269|PubMed:8621063, ECO:0000269|PubMed:8629002, ECO:0000269|PubMed:9036984, ECO:0000269|PubMed:9064343, ECO:0000269|PubMed:9252121, ECO:0000269|PubMed:9469421, ECO:0000269|PubMed:9480991, ECO:0000269|PubMed:9547345, ECO:0000269|PubMed:9573010, ECO:0000269|PubMed:9590210, ECO:0000269|PubMed:9601638}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, ECO:0000269|PubMed:12486102, ECO:0000269|PubMed:18984583, ECO:0000269|PubMed:2017160, ECO:0000269|PubMed:8530369};

Activity regulation: Subject to autoinhibition, mediated by intramolecular interactions between the SH2 domain and the C-terminal phosphotyrosine. Phosphorylation at Tyr-397 is required for optimal activity. Phosphorylated by CSK at Tyr-508; phosphorylation at Tyr-508 inhibits kinase activity. Kinase activity is modulated by dephosphorylation by PTPRC/CD45. Inhibited by dasatinib, PP2, and SU6656. {ECO:0000269|PubMed:10415030, ECO:0000269|PubMed:12486102, ECO:0000269|PubMed:18984583, ECO:0000269|PubMed:8530369}.

Subunit: Interacts with TEC. Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with LIME1 and with CD79A upon activation of the B-cell antigen receptor. Interacts with the B-cell receptor complex. Interacts with phosphorylated THEMIS2. Interacts with EPOR. Interacts with MS4A2/FCER1B. Interaction (via the SH2 and SH3 domains) with MUC1 is stimulated by IL7 and the subsequent phosphorylation increases the binding between MUC1 and CTNNB1/beta- catenin. Interacts with ADAM15. Interacts with NDFIP2 and more weakly with NDFIP1. Interacts with FASLG. Interacts with KIT. Interacts with HCLS1. Interacts with FCGR2B. Interacts with FCGR1A; the interaction may be indirect. Interacts with CD19, CD22, CD79A and CD79B. Interacts (via SH3 domain) with CBLC, PPP1R15A and PDE4A. Interacts with TGFB1I1. Interacts (via SH3 domain) with PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase; this interaction enhances phosphatidylinositol 3-kinase activity. Interacts with CSF2RB, the common subunit of the IL3, IL5 and CSF2 receptors. Interacts with PAG1; identified in a complex with PAG1 and STAT3. Interacts with ABL1. Interacts with PTPN6/SHP-1. Interacts (via SH3 domain) with SCIMP (via proline-rich region) (PubMed:28098138). This interaction facilitates the phosphorylation of SCIMP on 'Tyr-96', which enhances binding of SCIMP to TLR4, and consequently the phosphorylation of TLR4 in response to stimulation by lipopolysaccharide in macrophages (PubMed:28098138). Interacts with LPXN (via LD motif 3) and the interaction is induced upon B-cell antigen receptor (BCR) activation. Interacts (via SH3- domain) with ANKRD54 (via ankyrin repeat region) in an activation- independent status of LYN. Forms a multiprotein complex with ANKRD54 and HCLS1. Interacts (via SH2 and SH3 domains) with UNC119; leading to LYN activation (By similarity). Interacts with CD36. Interacts with LYN (PubMed:22496641). Interacts with SKAP1 and FYB1; this interaction promotes the phosphorylation of CLNK (PubMed:12681493). {ECO:0000250|UniProtKB:P07948, ECO:0000269|PubMed:10672044, ECO:0000269|PubMed:11517336, ECO:0000269|PubMed:12681493, ECO:0000269|PubMed:15335855, ECO:0000269|PubMed:16249387, ECO:0000269|PubMed:16272347, ECO:0000269|PubMed:16684964, ECO:0000269|PubMed:1702903, ECO:0000269|PubMed:17233630, ECO:0000269|PubMed:17640867, ECO:0000269|PubMed:19064729, ECO:0000269|PubMed:20644716, ECO:0000269|PubMed:22496641, ECO:0000269|PubMed:28098138, ECO:0000269|PubMed:7782294, ECO:0000269|PubMed:8128248, ECO:0000269|PubMed:8168489, ECO:0000269|PubMed:8621063, ECO:0000269|PubMed:9469421, ECO:0000269|PubMed:9573010}.

Subcellular location: Cell membrane {ECO:0000250}. Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}. Cytoplasm, perinuclear region {ECO:0000250}. Golgi apparatus {ECO:0000250}. Membrane {ECO:0000250|UniProtKB:P07948}; Lipid-anchor {ECO:0000250|UniProtKB:P07948}. Note=Accumulates in the nucleus by inhibition of Crm1-mediated nuclear export. Nuclear accumulation is increased by inhibition of its kinase activity. The trafficking from the Golgi apparatus to the cell membrane occurs in a kinase domain- dependent but kinase activity independent manner and is mediated by exocytic vesicular transport (By similarity). {ECO:0000250}.

Tissue specificity: Detected in bone marrow-derived monocytes and macrophages (at protein level) (PubMed:28098138, PubMed:2017160). Expressed predominantly in B-lymphoid and myeloid cells (PubMed:2017160). {ECO:0000269|PubMed:2017160, ECO:0000269|PubMed:28098138}.

Domain: The protein kinase domain plays an important role in its localization in the cell membrane. {ECO:0000250}.

Ptm: Ubiquitinated by CBL, leading to its degradation. {ECO:0000269|PubMed:15304502}.

Ptm: Phosphorylated on tyrosine residues in response to KIT signaling (By similarity). Autophosphorylated. Phosphorylation at Tyr-397 is required for optimal activity. Phosphorylation at Tyr-508 inhibits kinase activity. Phosphorylated at Tyr-508 by CSK. Dephosphorylated by PTPRC/CD45. Becomes rapidly phosphorylated upon activation of the B- cell receptor and the immunoglobulin receptor FCGR1A. {ECO:0000250, ECO:0000269|PubMed:10415030, ECO:0000269|PubMed:16272347, ECO:0000269|PubMed:9252121}.

Disruption phenotype: No visible phenotype at birth. B-cell development in the bone marrow proceeds normally, but mice have reduced numbers of peripheral B-cells, with a greater proportion of immature cells and an increased turnover rate. Dendritic cells also have a more immature phenotype. Mice develop severe asthma upon exposure to airborne antigen. Mice display elevated levels of serum IgM. Aging mice display strongly increased levels of myeloid cells, severe extramedullary hematoipoiesis and tend to develop monocyte/macrophage tumors. After about 16 weeks, mice begin to develop splenomegaly and glomerulonephritis, and display autoimmune antibodies. Their B-cells are hypersensitive to stimulation of the B-cell receptor, and display enhanced activation of the MAP kinase signaling pathway. Mice do not display an allergic response upon IgE receptor engagement. {ECO:0000269|PubMed:10594694, ECO:0000269|PubMed:11672542, ECO:0000269|PubMed:16034130, ECO:0000269|PubMed:7584145, ECO:0000269|PubMed:7585947, ECO:0000269|PubMed:9064343, ECO:0000269|PubMed:9252121}.

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-96'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (PubMed:28098138). Phosphorylates CLNK (PubMed:12681493). {ECO:0000250\|UniProtKB:P07948, ECO:0000269\|PubMed:10327049, ECO:0000269\|PubMed:10594694, ECO:0000269\|PubMed:10640270, ECO:0000269\|PubMed:10672044, ECO:0000269\|PubMed:11007759, ECO:0000269\|PubMed:11435302, ECO:0000269\|PubMed:11672542, ECO:0000269\|PubMed:12077122, ECO:0000269\|PubMed:12681493, ECO:0000269\|PubMed:12874221, ECO:0000269\|PubMed:14525964, ECO:0000269\|PubMed:14726379, ECO:0000269\|PubMed:15335855, ECO:0000269\|PubMed:16034130, ECO:0000269\|PubMed:16116174, ECO:0000269\|PubMed:16249387, ECO:0000269\|PubMed:16272347, ECO:0000269\|PubMed:16731527, ECO:0000269\|PubMed:17640867, ECO:0000269\|PubMed:19492092, ECO:0000269\|PubMed:20189992, ECO:0000269\|PubMed:20385881, ECO:0000269\|PubMed:28098138, ECO:0000269\|PubMed:7513017, ECO:0000269\|PubMed:7584145, ECO:0000269\|PubMed:7585947, ECO:0000269\|PubMed:8128248, ECO:0000269\|PubMed:8621063, ECO:0000269\|PubMed:8629002, ECO:0000269\|PubMed:9036984, ECO:0000269\|PubMed:9064343, ECO:0000269\|PubMed:9252121, ECO:0000269\|PubMed:9469421, ECO:0000269\|PubMed:9480991, ECO:0000269\|PubMed:9547345, ECO:0000269\|PubMed:9573010, ECO:0000269\|PubMed:9590210, ECO:0000269\|PubMed:9601638}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028, ECO:0000269\|PubMed:12486102, ECO:0000269\|PubMed:18984583, ECO:0000269\|PubMed:2017160, ECO:0000269\|PubMed:8530369};
Activity regulation:		Subject to autoinhibition, mediated by intramolecular interactions between the SH2 domain and the C-terminal phosphotyrosine. Phosphorylation at Tyr-397 is required for optimal activity. Phosphorylated by CSK at Tyr-508; phosphorylation at Tyr-508 inhibits kinase activity. Kinase activity is modulated by dephosphorylation by PTPRC/CD45. Inhibited by dasatinib, PP2, and SU6656. {ECO:0000269\|PubMed:10415030, ECO:0000269\|PubMed:12486102, ECO:0000269\|PubMed:18984583, ECO:0000269\|PubMed:8530369}.
Subunit:		Interacts with TEC. Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated). Interacts with LIME1 and with CD79A upon activation of the B-cell antigen receptor. Interacts with the B-cell receptor complex. Interacts with phosphorylated THEMIS2. Interacts with EPOR. Interacts with MS4A2/FCER1B. Interaction (via the SH2 and SH3 domains) with MUC1 is stimulated by IL7 and the subsequent phosphorylation increases the binding between MUC1 and CTNNB1/beta- catenin. Interacts with ADAM15. Interacts with NDFIP2 and more weakly with NDFIP1. Interacts with FASLG. Interacts with KIT. Interacts with HCLS1. Interacts with FCGR2B. Interacts with FCGR1A; the interaction may be indirect. Interacts with CD19, CD22, CD79A and CD79B. Interacts (via SH3 domain) with CBLC, PPP1R15A and PDE4A. Interacts with TGFB1I1. Interacts (via SH3 domain) with PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase; this interaction enhances phosphatidylinositol 3-kinase activity. Interacts with CSF2RB, the common subunit of the IL3, IL5 and CSF2 receptors. Interacts with PAG1; identified in a complex with PAG1 and STAT3. Interacts with ABL1. Interacts with PTPN6/SHP-1. Interacts (via SH3 domain) with SCIMP (via proline-rich region) (PubMed:28098138). This interaction facilitates the phosphorylation of SCIMP on 'Tyr-96', which enhances binding of SCIMP to TLR4, and consequently the phosphorylation of TLR4 in response to stimulation by lipopolysaccharide in macrophages (PubMed:28098138). Interacts with LPXN (via LD motif 3) and the interaction is induced upon B-cell antigen receptor (BCR) activation. Interacts (via SH3- domain) with ANKRD54 (via ankyrin repeat region) in an activation- independent status of LYN. Forms a multiprotein complex with ANKRD54 and HCLS1. Interacts (via SH2 and SH3 domains) with UNC119; leading to LYN activation (By similarity). Interacts with CD36. Interacts with LYN (PubMed:22496641). Interacts with SKAP1 and FYB1; this interaction promotes the phosphorylation of CLNK (PubMed:12681493). {ECO:0000250\|UniProtKB:P07948, ECO:0000269\|PubMed:10672044, ECO:0000269\|PubMed:11517336, ECO:0000269\|PubMed:12681493, ECO:0000269\|PubMed:15335855, ECO:0000269\|PubMed:16249387, ECO:0000269\|PubMed:16272347, ECO:0000269\|PubMed:16684964, ECO:0000269\|PubMed:1702903, ECO:0000269\|PubMed:17233630, ECO:0000269\|PubMed:17640867, ECO:0000269\|PubMed:19064729, ECO:0000269\|PubMed:20644716, ECO:0000269\|PubMed:22496641, ECO:0000269\|PubMed:28098138, ECO:0000269\|PubMed:7782294, ECO:0000269\|PubMed:8128248, ECO:0000269\|PubMed:8168489, ECO:0000269\|PubMed:8621063, ECO:0000269\|PubMed:9469421, ECO:0000269\|PubMed:9573010}.
Subcellular location:		Cell membrane {ECO:0000250}. Nucleus {ECO:0000250}. Cytoplasm {ECO:0000250}. Cytoplasm, perinuclear region {ECO:0000250}. Golgi apparatus {ECO:0000250}. Membrane {ECO:0000250\|UniProtKB:P07948}; Lipid-anchor {ECO:0000250\|UniProtKB:P07948}. Note=Accumulates in the nucleus by inhibition of Crm1-mediated nuclear export. Nuclear accumulation is increased by inhibition of its kinase activity. The trafficking from the Golgi apparatus to the cell membrane occurs in a kinase domain- dependent but kinase activity independent manner and is mediated by exocytic vesicular transport (By similarity). {ECO:0000250}.
Tissue specificity:		Detected in bone marrow-derived monocytes and macrophages (at protein level) (PubMed:28098138, PubMed:2017160). Expressed predominantly in B-lymphoid and myeloid cells (PubMed:2017160). {ECO:0000269\|PubMed:2017160, ECO:0000269\|PubMed:28098138}.
Domain:		The protein kinase domain plays an important role in its localization in the cell membrane. {ECO:0000250}.
Ptm:		Ubiquitinated by CBL, leading to its degradation. {ECO:0000269\|PubMed:15304502}.
Ptm:		Phosphorylated on tyrosine residues in response to KIT signaling (By similarity). Autophosphorylated. Phosphorylation at Tyr-397 is required for optimal activity. Phosphorylation at Tyr-508 inhibits kinase activity. Phosphorylated at Tyr-508 by CSK. Dephosphorylated by PTPRC/CD45. Becomes rapidly phosphorylated upon activation of the B- cell receptor and the immunoglobulin receptor FCGR1A. {ECO:0000250, ECO:0000269\|PubMed:10415030, ECO:0000269\|PubMed:16272347, ECO:0000269\|PubMed:9252121}.
Disruption phenotype:		No visible phenotype at birth. B-cell development in the bone marrow proceeds normally, but mice have reduced numbers of peripheral B-cells, with a greater proportion of immature cells and an increased turnover rate. Dendritic cells also have a more immature phenotype. Mice develop severe asthma upon exposure to airborne antigen. Mice display elevated levels of serum IgM. Aging mice display strongly increased levels of myeloid cells, severe extramedullary hematoipoiesis and tend to develop monocyte/macrophage tumors. After about 16 weeks, mice begin to develop splenomegaly and glomerulonephritis, and display autoimmune antibodies. Their B-cells are hypersensitive to stimulation of the B-cell receptor, and display enhanced activation of the MAP kinase signaling pathway. Mice do not display an allergic response upon IgE receptor engagement. {ECO:0000269\|PubMed:10594694, ECO:0000269\|PubMed:11672542, ECO:0000269\|PubMed:16034130, ECO:0000269\|PubMed:7584145, ECO:0000269\|PubMed:7585947, ECO:0000269\|PubMed:9064343, ECO:0000269\|PubMed:9252121}.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. {ECO:0000255\|PROSITE-ProRule:PRU00159}.