UniProt functional annotation for Q2MKA7



	UniProt functional annotation for Q2MKA7

UniProt code: Q2MKA7.

Organism: Homo sapiens (Human).

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

Function: Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors (PubMed:29769720). Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin- dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway. Has a essential roles in ovary determination. Regulates Wnt signaling by antagonizing DKK1/KREM1- mediated internalization of LRP6 through an interaction with KREM1 (PubMed:17804805). {ECO:0000269|PubMed:16109882, ECO:0000269|PubMed:17804805, ECO:0000269|PubMed:21727895, ECO:0000269|PubMed:21909076, ECO:0000269|PubMed:22575959, ECO:0000269|PubMed:22615920, ECO:0000269|PubMed:22815884, ECO:0000269|PubMed:23756652, ECO:0000269|PubMed:23809763, ECO:0000269|PubMed:29769720}.

Subunit: Interacts with the extracellular domain of FZD8 and LRP6. It however does not form a ternary complex with FZD8 and LRP6. Interacts with WNT1. Binds heparin (By similarity). Interacts with ZNRF3; promoting indirect interaction between ZNRF3 and LGR4 and membrane clearance of ZNRF3. Interacts with LGR4, LGR5 and LGR6. Identified in a complex composed of RNF43, LGR5 and RSPO1. Interacts (via FU repeats) with KREM1 (PubMed:17804805). {ECO:0000250|UniProtKB:Q9Z132, ECO:0000269|PubMed:17804805, ECO:0000269|PubMed:21727895, ECO:0000269|PubMed:21909076, ECO:0000269|PubMed:22575959, ECO:0000269|PubMed:22615920, ECO:0000269|PubMed:22815884, ECO:0000269|PubMed:23756651, ECO:0000269|PubMed:23756652, ECO:0000269|PubMed:23809763}.

Subcellular location: Secreted {ECO:0000250|UniProtKB:Q9Z132}. Nucleus {ECO:0000250|UniProtKB:Q9Z132}. Note=Seems to mainly localize to nucleoli. {ECO:0000250|UniProtKB:Q9Z132}.

Tissue specificity: Abundantly expressed in adrenal glands, ovary, testis, thyroid and trachea but not in bone marrow, spinal cord, stomach, leukocytes colon, small intestine, prostate, thymus and spleen. {ECO:0000269|PubMed:17041600}.

Domain: The FU repeats are required for activation and stabilization of beta-catenin. {ECO:0000250}.

Disease: Keratoderma, palmoplantar, with squamous cell carcinoma of skin and sex reversal (PKKSCC) [MIM:610644]: A recessive syndrome characterized by XX (female to male) SRY-independent sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. {ECO:0000269|PubMed:17041600}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: Upon injection into mice, it induces rapid onset of crypt cell proliferation involving beta-catenin stabilization. It also displays efficacy in a model of chemotherapy-induced intestinal mucositis suggesting possible therapeutic application in gastrointestinal diseases.

Similarity: Belongs to the R-spondin family. {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:		Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors (PubMed:29769720). Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin- dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway. Has a essential roles in ovary determination. Regulates Wnt signaling by antagonizing DKK1/KREM1- mediated internalization of LRP6 through an interaction with KREM1 (PubMed:17804805). {ECO:0000269\|PubMed:16109882, ECO:0000269\|PubMed:17804805, ECO:0000269\|PubMed:21727895, ECO:0000269\|PubMed:21909076, ECO:0000269\|PubMed:22575959, ECO:0000269\|PubMed:22615920, ECO:0000269\|PubMed:22815884, ECO:0000269\|PubMed:23756652, ECO:0000269\|PubMed:23809763, ECO:0000269\|PubMed:29769720}.


Subunit:		Interacts with the extracellular domain of FZD8 and LRP6. It however does not form a ternary complex with FZD8 and LRP6. Interacts with WNT1. Binds heparin (By similarity). Interacts with ZNRF3; promoting indirect interaction between ZNRF3 and LGR4 and membrane clearance of ZNRF3. Interacts with LGR4, LGR5 and LGR6. Identified in a complex composed of RNF43, LGR5 and RSPO1. Interacts (via FU repeats) with KREM1 (PubMed:17804805). {ECO:0000250\|UniProtKB:Q9Z132, ECO:0000269\|PubMed:17804805, ECO:0000269\|PubMed:21727895, ECO:0000269\|PubMed:21909076, ECO:0000269\|PubMed:22575959, ECO:0000269\|PubMed:22615920, ECO:0000269\|PubMed:22815884, ECO:0000269\|PubMed:23756651, ECO:0000269\|PubMed:23756652, ECO:0000269\|PubMed:23809763}.
Subcellular location:		Secreted {ECO:0000250\|UniProtKB:Q9Z132}. Nucleus {ECO:0000250\|UniProtKB:Q9Z132}. Note=Seems to mainly localize to nucleoli. {ECO:0000250\|UniProtKB:Q9Z132}.
Tissue specificity:		Abundantly expressed in adrenal glands, ovary, testis, thyroid and trachea but not in bone marrow, spinal cord, stomach, leukocytes colon, small intestine, prostate, thymus and spleen. {ECO:0000269\|PubMed:17041600}.
Domain:		The FU repeats are required for activation and stabilization of beta-catenin. {ECO:0000250}.
Disease:		Keratoderma, palmoplantar, with squamous cell carcinoma of skin and sex reversal (PKKSCC) [MIM:610644]: A recessive syndrome characterized by XX (female to male) SRY-independent sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. {ECO:0000269\|PubMed:17041600}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		Upon injection into mice, it induces rapid onset of crypt cell proliferation involving beta-catenin stabilization. It also displays efficacy in a model of chemotherapy-induced intestinal mucositis suggesting possible therapeutic application in gastrointestinal diseases.
Similarity:		Belongs to the R-spondin family. {ECO:0000305}.