UniProt functional annotation for Q9NQB0



	UniProt functional annotation for Q9NQB0

UniProt code: Q9NQB0.

Organism: Homo sapiens (Human).

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

Function: Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner. Acts as repressor in the absence of CTNNB1, and as activator in its presence. Activates transcription from promoters with several copies of the Tcf motif 5'-CCTTTGATC-3' in the presence of CTNNB1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by TCF7L2/TCF4 and CTNNB1. Expression of dominant-negative mutants results in cell-cycle arrest in G1. Necessary for the maintenance of the epithelial stem-cell compartment of the small intestine. {ECO:0000269|PubMed:12408868, ECO:0000269|PubMed:12727872, ECO:0000269|PubMed:19443654, ECO:0000269|PubMed:22699938, ECO:0000269|PubMed:9727977}.

Subunit: Interacts with TGFB1I1 (By similarity). Interacts with CTNNB1 (via the armadillo repeat); forms stable transcription complex (PubMed:9065401, PubMed:9916915, PubMed:10080941, PubMed:19816403, PubMed:28829046, PubMed:29739711, PubMed:17052462). Interacts with EP300. Interacts with NLK. Interacts with CCDC85B (probably through the HMG box); prevents interaction with CTNNB1. Interacts with TNIK. Interacts with MAD2L2; prevents TCF7L2/TCF4 binding to promZIPK/DAPK3oters, negatively modulating its transcriptional activity. Interacts with ZIPK/DAPK3. Interacts with XIAP/BIRC4 and TLE3. Interacts with DDIT3/CHOP. The CTNNB1 and TCF7L2/TCF4 complex interacts with PML (isoform PML-4). Identified in a complex with CTNNB1 and FERMT2. Interacts with SPIN1 (PubMed:22258766, PubMed:24589551, PubMed:29061846). Interacts with C11orf84/SPINDOC in a SPIN1-dependent manner (PubMed:29061846). {ECO:0000250|UniProtKB:Q924A0, ECO:0000269|PubMed:10080941, ECO:0000269|PubMed:11266540, ECO:0000269|PubMed:12446687, ECO:0000269|PubMed:12556497, ECO:0000269|PubMed:12727872, ECO:0000269|PubMed:16434966, ECO:0000269|PubMed:16714285, ECO:0000269|PubMed:17052462, ECO:0000269|PubMed:17873903, ECO:0000269|PubMed:19443654, ECO:0000269|PubMed:19816403, ECO:0000269|PubMed:21454679, ECO:0000269|PubMed:22155184, ECO:0000269|PubMed:22258766, ECO:0000269|PubMed:22304967, ECO:0000269|PubMed:22699938, ECO:0000269|PubMed:24589551, ECO:0000269|PubMed:28829046, ECO:0000269|PubMed:29061846, ECO:0000269|PubMed:29739711, ECO:0000269|PubMed:9065401, ECO:0000269|PubMed:9916915}.

Subcellular location: Nucleus, PML body {ECO:0000269|PubMed:12727872, ECO:0000269|PubMed:22699938, ECO:0000269|PubMed:9916915}. Note=Diffuse pattern. Colocalizes with SUMO1 and PIAS4 in a subset of PML (promyelocytic leukemia) nuclear bodies.

Tissue specificity: Detected in epithelium from small intestine, with the highest expression at the top of the crypts and a gradient of expression from crypt to villus. Detected in colon epithelium and colon cancer, and in epithelium from mammary gland and carcinomas derived therefrom. {ECO:0000269|PubMed:9916915}.

Developmental stage: Highly expressed in crypt regions and barely detectable in villi in epithelium from fetal small intestine at week 16. At week 22 expression in villi had increased strongly.

Domain: The promoter-specific activation domain interacts with the transcriptional coactivator EP300.

Ptm: In vitro, phosphorylated by TNIK. {ECO:0000269|PubMed:12556497}.

Ptm: Phosphorylated at Thr-201 and/or Thr-212 by NLK. Phosphorylation by NLK at these sites inhibits DNA-binding by TCF7L2/TCF4, thereby preventing transcriptional activation of target genes of the canonical Wnt/beta-catenin signaling pathway. {ECO:0000269|PubMed:12556497}.

Ptm: Polysumoylated. Sumoylation is enhanced by PIAS family members and desumoylation is enhanced by SENP2. Sumoylation/desumoylation regulates TCF7L2/TCF4 transcription activity in the Wnt/beta-catenin signaling pathway without altering interaction with CTNNB1 nor binding to DNA. {ECO:0000269|PubMed:12727872}.

Disease: Note=Constitutive activation and subsequent transactivation of target genes may lead to the maintenance of stem-cell characteristics (cycling and longevity) in cells that should normally undergo terminal differentiation and constitute the primary transforming event in colorectal cancer (CRC).

Disease: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:16415884, ECO:0000269|PubMed:24390345}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 12]: Low expression in pancreas and colon. {ECO:0000305}.

Miscellaneous: [Isoform 13]: Common splicing form, lowest expression in skeletal muscle. {ECO:0000305}.

Miscellaneous: [Isoform 14]: High transcriptional activity. Major isoform in liver. {ECO:0000305}.

Similarity: Belongs to the TCF/LEF 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:		Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner. Acts as repressor in the absence of CTNNB1, and as activator in its presence. Activates transcription from promoters with several copies of the Tcf motif 5'-CCTTTGATC-3' in the presence of CTNNB1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by TCF7L2/TCF4 and CTNNB1. Expression of dominant-negative mutants results in cell-cycle arrest in G1. Necessary for the maintenance of the epithelial stem-cell compartment of the small intestine. {ECO:0000269\|PubMed:12408868, ECO:0000269\|PubMed:12727872, ECO:0000269\|PubMed:19443654, ECO:0000269\|PubMed:22699938, ECO:0000269\|PubMed:9727977}.


Subunit:		Interacts with TGFB1I1 (By similarity). Interacts with CTNNB1 (via the armadillo repeat); forms stable transcription complex (PubMed:9065401, PubMed:9916915, PubMed:10080941, PubMed:19816403, PubMed:28829046, PubMed:29739711, PubMed:17052462). Interacts with EP300. Interacts with NLK. Interacts with CCDC85B (probably through the HMG box); prevents interaction with CTNNB1. Interacts with TNIK. Interacts with MAD2L2; prevents TCF7L2/TCF4 binding to promZIPK/DAPK3oters, negatively modulating its transcriptional activity. Interacts with ZIPK/DAPK3. Interacts with XIAP/BIRC4 and TLE3. Interacts with DDIT3/CHOP. The CTNNB1 and TCF7L2/TCF4 complex interacts with PML (isoform PML-4). Identified in a complex with CTNNB1 and FERMT2. Interacts with SPIN1 (PubMed:22258766, PubMed:24589551, PubMed:29061846). Interacts with C11orf84/SPINDOC in a SPIN1-dependent manner (PubMed:29061846). {ECO:0000250\|UniProtKB:Q924A0, ECO:0000269\|PubMed:10080941, ECO:0000269\|PubMed:11266540, ECO:0000269\|PubMed:12446687, ECO:0000269\|PubMed:12556497, ECO:0000269\|PubMed:12727872, ECO:0000269\|PubMed:16434966, ECO:0000269\|PubMed:16714285, ECO:0000269\|PubMed:17052462, ECO:0000269\|PubMed:17873903, ECO:0000269\|PubMed:19443654, ECO:0000269\|PubMed:19816403, ECO:0000269\|PubMed:21454679, ECO:0000269\|PubMed:22155184, ECO:0000269\|PubMed:22258766, ECO:0000269\|PubMed:22304967, ECO:0000269\|PubMed:22699938, ECO:0000269\|PubMed:24589551, ECO:0000269\|PubMed:28829046, ECO:0000269\|PubMed:29061846, ECO:0000269\|PubMed:29739711, ECO:0000269\|PubMed:9065401, ECO:0000269\|PubMed:9916915}.
Subcellular location:		Nucleus, PML body {ECO:0000269\|PubMed:12727872, ECO:0000269\|PubMed:22699938, ECO:0000269\|PubMed:9916915}. Note=Diffuse pattern. Colocalizes with SUMO1 and PIAS4 in a subset of PML (promyelocytic leukemia) nuclear bodies.
Tissue specificity:		Detected in epithelium from small intestine, with the highest expression at the top of the crypts and a gradient of expression from crypt to villus. Detected in colon epithelium and colon cancer, and in epithelium from mammary gland and carcinomas derived therefrom. {ECO:0000269\|PubMed:9916915}.
Developmental stage:		Highly expressed in crypt regions and barely detectable in villi in epithelium from fetal small intestine at week 16. At week 22 expression in villi had increased strongly.
Domain:		The promoter-specific activation domain interacts with the transcriptional coactivator EP300.
Ptm:		In vitro, phosphorylated by TNIK. {ECO:0000269\|PubMed:12556497}.
Ptm:		Phosphorylated at Thr-201 and/or Thr-212 by NLK. Phosphorylation by NLK at these sites inhibits DNA-binding by TCF7L2/TCF4, thereby preventing transcriptional activation of target genes of the canonical Wnt/beta-catenin signaling pathway. {ECO:0000269\|PubMed:12556497}.
Ptm:		Polysumoylated. Sumoylation is enhanced by PIAS family members and desumoylation is enhanced by SENP2. Sumoylation/desumoylation regulates TCF7L2/TCF4 transcription activity in the Wnt/beta-catenin signaling pathway without altering interaction with CTNNB1 nor binding to DNA. {ECO:0000269\|PubMed:12727872}.
Disease:		Note=Constitutive activation and subsequent transactivation of target genes may lead to the maintenance of stem-cell characteristics (cycling and longevity) in cells that should normally undergo terminal differentiation and constitute the primary transforming event in colorectal cancer (CRC).
Disease:		Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269\|PubMed:16415884, ECO:0000269\|PubMed:24390345}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 12]: Low expression in pancreas and colon. {ECO:0000305}.
Miscellaneous:		[Isoform 13]: Common splicing form, lowest expression in skeletal muscle. {ECO:0000305}.
Miscellaneous:		[Isoform 14]: High transcriptional activity. Major isoform in liver. {ECO:0000305}.
Similarity:		Belongs to the TCF/LEF family. {ECO:0000305}.