PDX1

Summary

PDX1 (pancreatic and duodenal homeobox 1, HGNC:6107) is a protein-coding gene on chromosome 13q12.2, encoding Pancreas/duodenum homeobox protein 1 (P52945). Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription.

The protein encoded by this gene is a transcriptional activator of several genes, including insulin, somatostatin, glucokinase, islet amyloid polypeptide, and glucose transporter type 2. The encoded nuclear protein is involved in the early development of the pancreas and plays a major role in glucose-dependent regulation of insulin gene expression. Defects in this gene are a cause of pancreatic agenesis, which can lead to early-onset insulin-dependent diabetes mellitus (IDDM), as well as maturity onset diabetes of the young type 4 (MODY4).

Source: NCBI Gene 3651 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pancreatic agenesis 1 (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 262 total — 3 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 1
• Transcription factor: yes — 95 downstream targets (CollecTRI)
• MANE Select transcript: NM_000209

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6107
Approved symbol	PDX1
Name	pancreatic and duodenal homeobox 1
Location	13q12.2
Locus type	gene with protein product
Status	Approved
Aliases	IDX-1, STF-1, PDX-1, MODY4, GSF, IUF-1
Ensembl gene	ENSG00000139515
Ensembl biotype	protein_coding
OMIM	600733
Entrez	3651

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000381033

RefSeq mRNA: 1 — MANE Select: NM_000209 NM_000209

CCDS: CCDS9327

Canonical transcript exons

ENST00000381033 — 2 exons

Exon	Start	End
ENSE00000938517	27924256	27926313
ENSE00001487306	27920000	27920544

Expression profiles

Bgee: expression breadth broad, 30 present calls, max score 90.49.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.9487 / max 485.8490, expressed in 83 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134542	3.0186	77
134541	0.5727	57
134543	0.3116	35
134544	0.0458	23

Top tissues by expression

276 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	90.49	gold quality
pancreas	UBERON:0001264	81.61	gold quality
body of pancreas	UBERON:0001150	79.49	gold quality
duodenum	UBERON:0002114	75.72	gold quality
tendon of biceps brachii	UBERON:0008188	69.36	gold quality
gall bladder	UBERON:0002110	65.41	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	63.83	gold quality
vena cava	UBERON:0004087	63.75	gold quality
upper arm skin	UBERON:0004263	60.84	gold quality
buccal mucosa cell	CL:0002336	60.76	gold quality
cerebellar vermis	UBERON:0004720	60.61	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	60.22	gold quality
palpebral conjunctiva	UBERON:0001812	59.86	gold quality
jejunal mucosa	UBERON:0000399	59.18	gold quality
endothelial cell	CL:0000115	58.62	gold quality
myocardium	UBERON:0002349	58.35	gold quality
trabecular bone tissue	UBERON:0002483	58.24	gold quality
secondary oocyte	CL:0000655	57.81	gold quality
cartilage tissue	UBERON:0002418	56.83	gold quality
lateral nuclear group of thalamus	UBERON:0002736	55.89	gold quality
lateral globus pallidus	UBERON:0002476	55.85	gold quality
quadriceps femoris	UBERON:0001377	55.76	gold quality
nasal cavity epithelium	UBERON:0005384	55.42	gold quality
thymus	UBERON:0002370	55.36	gold quality
vastus lateralis	UBERON:0001379	55.15	gold quality
oocyte	CL:0000023	54.10	gold quality
colonic epithelium	UBERON:0000397	53.49	gold quality
middle temporal gyrus	UBERON:0002771	53.14	gold quality
entorhinal cortex	UBERON:0002728	53.12	gold quality
postcentral gyrus	UBERON:0002581	53.07	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	542.66
E-GEOD-81547	yes	148.51
E-GEOD-81608	yes	21.58
E-ENAD-27	yes	13.71
E-GEOD-83139	yes	10.46
E-ANND-3	yes	4.20

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

95 targets.

Target	Regulation
ABCC8	Activation
ACAT1
ADA	Activation
ADAM2
AFP	Activation
AGXT
AXIN1
CCNA2	Activation
CD74
CDK5
CDKN1B
CEBPB	Repression
CEL
CELA1	Activation
CHGB
CHKA
CLU	Activation
CPE	Activation
CSNK2A1
CSNK2A2
CTNNB1	Repression
DMPK
DNER
FABP1
FFAR1	Unknown
FGFR1	Unknown
FOXA2
G6PC2	Unknown
GCG	Activation
GCK	Activation

JASPAR motifs

Motif	Name	Family
MA0132.2	PDX1	HOX
MA0132.3	PDX1	HOX

JASPAR matrix evidence (PMIDs): PMID:18585360

Upstream regulators (CollecTRI, top): ATF3, ATF6, CEBPB, CNBP, EGR1, FOXA1, FOXA2, FOXO1, HCFC1, HNF1A, HNF1B, KLF11, MAF, MAFA, MAFB, MXD1, NEUROD1, NKX6-1, NR0B2, NR1H2, NR3C1, ONECUT1, PAX6, PBX1, PDX1, PPARA, PPARG, PTF1A, RBPJ, SOX9, SP1, SREBF1, SSRP1, TCF3, USF1, USF2, ZGLP1, ZNF236

miRNA regulators (miRDB)

84 targeting PDX1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-11181-3P	99.75	66.38	2205

Literature-anchored findings (GeneRIF, showing 40)

• differentiation factor during embryogenesis and a regulator of islet cell physiology in mature islet cells (PMID:11834421)
• Conserved sequences in a tissue-specific regulatory region of the pdx-1 gene mediate transcription in Pancreatic beta cells (PMID:12052878)
• differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors (PMID:12124776)
• Cell-specific expression of the glucagon gene can only occur when Pdx1 expression extinguishes from the early alpha cell precursor. (PMID:12783165)
• Re-expression of PDX-1 may represent a return to a more de-differentiated state by more aggressive pancreatic cancers (PMID:12947327)
• insulin promoter factor 1 level is critical for human pancreas formation (PMID:12970316)
• Analysis of the regulatory region of the LRH-1 gene demonstrated the presence of three functional binding sites for PDX1. (PMID:12972592)
• PDX-1 represents a candidate switch factor for glandular exocrine and endocrine transdifferentiation in chronic gastritis and that an impaired parietal cell differentiation might play a key role in disturbed gastric morphogenic processes. (PMID:14631368)
• E224K showed reduced transactivation activity. IPF1 mutations leading to synthesis of mutant protein may contribute to development of familial early-onset diabetes/maturity-onset diabetes of young in Indo-Trinidadians. (PMID:14764823)
• PDX-1 is activated at a specific binding site in the human insulin gene (PMID:15028719)
• the effect of pdx-1 expression during in vitro differentiation of embryonic stem cells (PMID:15047618)
• Stable overexpression of pancreatic duodenal homeobox-1 results in repression of the endogenous human lactase-phlorizin hydrolase gene in differentiated Caco-2 cells (PMID:15107297)
• Polymorphism D76N does not confer sussceptibility to type 2 diabettes. (PMID:15170499)
• Hepatic regeneration and enforced PDX-1 expression accelerate transdifferentiation in liver. (PMID:15300214)
• These data suggest that mechanism of transduction of PDX-1 protein is by endocytosis and subsequent release from the endosome homogeneously in cytoplasm and nuclei. (PMID:15896300)
• co-expression and functional synergism of these beta-cell enriched transactivators, MafA, Pdx1, and Beta2, are critical for establishing the beta-cell-specific and efficient expression of the insulin gene. (PMID:15993959)
• the P33T IPF1 mutation may provide an increased susceptibility to the development of gestational diabetes and MODY4 in the Italy-6 pedigree (PMID:16092045)
• Pdx-1 plays a novel role in linking H3-Lys-4 dimethylation and pol II elongation to insulin transcription (PMID:16141209)
• The common alleles of regulatory variants in the 5’ enhancer and promoter regions of the IPF1 gene increase susceptibility to type 2 diabetes among African American individuals. (PMID:16229747)
• Analysis of both exons of the Ipf-1 coding sequence from the presented patient’s genomic DNA did not identify a mutation. (PMID:16390394)
• PDX-1 proteins are rapidly internalized by lipid raft-dependent macropinocytosis in HeLa cells. (PMID:16405074)
• IPF1/PDX1 protein can be phosphorylated in vivo in pancreatic beta-cells; this phosphorylation marks the protein for degradation by the proteasome machinery. (PMID:16407209)
• The overexpression of Pdx1 enhanced expression of pancreatic enriched genes, induction of insulin expression may require additional signals that are only present in vivo. (PMID:16675598)
• Mutations in a pedigree reveals in a point mutation, increasing susceptibility to type 2 diabetes. (PMID:16741735)
• The putative pancreatic stem cells expressed pdx-1 and nestin. (PMID:16874866)
• InsCCG243 does not act in a dominant, highly penetrant fashion in African Americans and is not a significant risk factor for type 2 diabetes in this population. (PMID:17003361)
• Interaction of endogenous PDX-1 and PCIF1 in MIN6 insulinoma cells, is demonstarted. (PMID:17126328)
• Ex vivo lentiviral-mediated PDX1 expression in isolated adult liver cells represents a potential model for type 1 diabetes mellitus therapy. (PMID:17131142)
• Human bone marrow-derived mesenchymal stem cells (hMSCs) could be induced to differentiate into functional insulin-producing cells by introduction of the pancreatic duodenal homeobox-1 (PDX-1). (PMID:17226789)
• A study evaluating the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes is presented. (PMID:17327436)
• possible relationship between PDX-1 and the state of islet proliferation, islet-to-ductal transdifferentiation, apoptosis, and the expression of SSTRs (PMID:17583748)
• D76N IPF1 is not contributing to type 2 diabete in early-onset or late-onset cohorts in the currently present worldwide dataset (Meta-analysis) (PMID:17592437)
• This study suggests a dual role for PDX-1 in liver: inducing hepatic dedifferentiation and activating the pancreatic lineage. (PMID:17705277)
• Activin B is a potent inducer of Pdx1 as well as Shh in differentiating embryonic stem cell derived embryoid bodies (PMID:17761145)
• The up-regulation of PDX-1 may be an important mechanism in the induction of the Ulcer-associated cell lineage in Crohn’s disease. (PMID:17957487)
• The addition of betacellulin and nicotinamide sustained PDX1 expression and induced beta-cell differentiation. C-peptide-a genuine marker of de novo insulin production-was identified in the differentiated cells. (PMID:18060872)
• Anomalous migration of Pdx-1 on SDS-PAGE does not result from post-translational modifications. (PMID:18361919)
• PDX1 expression is lost in gastric cancers. Its effect on cell proliferation/apoptosis, migration and tumor formation in vitro and in vivo suggested that this protein functions as a putative tumor suppressor in gastric cancer. (PMID:18477649)
• Under diabetic conditions, expression and/or activities of PDX-1 and MafA in beta-cells are reduced [REVIEW]. (PMID:18508668)
• Significance of large Maf proteins to Pdx1 expression in beta cells, and in particular MafB during pancreatic development. (PMID:18522939)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Pdx1	ENSMUSG00000029644
rattus_norvegicus	Pdx1	ENSRNOG00000046458

Paralogs (42): HOXA11 (ENSG00000005073), HOXC8 (ENSG00000037965), HOXA1 (ENSG00000105991), HOXA2 (ENSG00000105996), HOXA3 (ENSG00000105997), HOXA5 (ENSG00000106004), HOXA6 (ENSG00000106006), HOXA13 (ENSG00000106031), TLX1 (ENSG00000107807), HOXB6 (ENSG00000108511), TLX2 (ENSG00000115297), HOXB8 (ENSG00000120068), HOXB5 (ENSG00000120075), HOXB3 (ENSG00000120093), HOXB1 (ENSG00000120094), HOXA7 (ENSG00000122592), HOXC13 (ENSG00000123364), HOXC11 (ENSG00000123388), HOXC12 (ENSG00000123407), HOXD1 (ENSG00000128645), HOXD3 (ENSG00000128652), HOXD9 (ENSG00000128709), HOXD10 (ENSG00000128710), HOXD11 (ENSG00000128713), HOXD13 (ENSG00000128714), HOXB13 (ENSG00000159184), TLX3 (ENSG00000164438), HOXD4 (ENSG00000170166), HOXD12 (ENSG00000170178), HOXB9 (ENSG00000170689), HOXC5 (ENSG00000172789), HOXB2 (ENSG00000173917), HOXD8 (ENSG00000175879), GSX2 (ENSG00000180613), HOXC9 (ENSG00000180806), HOXC10 (ENSG00000180818), HOXB4 (ENSG00000182742), HOXA4 (ENSG00000197576), HOXC6 (ENSG00000197757), HOXC4 (ENSG00000198353)

Protein

Protein identifiers

Pancreas/duodenum homeobox protein 1 — P52945 (reviewed: P52945)

Alternative names: Glucose-sensitive factor, Insulin promoter factor 1, Insulin upstream factor 1, Islet/duodenum homeobox-1, Somatostatin-transactivating factor 1

All UniProt accessions (1): P52945

UniProt curated annotations — full annotation on UniProt →

Function. Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription. Particularly involved in glucose-dependent regulation of insulin gene transcription. As part of a PDX1:PBX1b:MEIS2b complex in pancreatic acinar cells is involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element. Binds preferentially the DNA motif 5’-[CT]TAAT[TG]-3’. During development, specifies the early pancreatic epithelium, permitting its proliferation, branching and subsequent differentiation. At adult stage, required for maintaining the hormone-producing phenotype of the beta-cell.

Subunit / interactions. Interacts with the basic helix-loop-helix domains of TCF3(E47) and NEUROD1 and with HMG-I(Y). Interacts with SPOP. Interacts with the methyltransferase SETD7. Part of a PDX1:PBX1b:MEIS2b complex.

Subcellular location. Nucleus. Cytoplasm. Cytosol.

Tissue specificity. Duodenum and pancreas (Langerhans islet beta cells and small subsets of endocrine non-beta-cells, at low levels in acinar cells).

Post-translational modifications. Phosphorylated by the SAPK2 pathway at high intracellular glucose concentration. Phosphorylated by HIPK2 on Ser-268 upon glucose accumulation. This phosphorylation mediates subnuclear localization shifting. Phosphorylation by PASK may lead to translocation into the cytosol.

Disease relevance. Pancreatic agenesis 1 (PAGEN1) [MIM:260370] A disease characterized by isolated hypoplasia or agenesis of the pancreas, pancreatic beta-cell failure resulting in neonatal insulin-dependent diabetes mellitus, and exocrine pancreatic insufficiency. The disease is caused by variants affecting the gene represented in this entry. Type 2 diabetes mellitus (T2D) [MIM:125853] A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to 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. Disease susceptibility is associated with variants affecting the gene represented in this entry. Maturity-onset diabetes of the young 4 (MODY4) [MIM:606392] A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Antp-type hexapeptide mediates heterodimerization with PBX on a regulatory element of the somatostatin promoter. The homeodomain, which contains the nuclear localization signal, not only mediates DNA-binding, but also acts as a protein-protein interaction domain for TCF3(E47), NEUROD1 and HMG-I(Y).

Miscellaneous. According to PubMed:16141209, it may be methylated by SETD7 in vitro. However, the relevance of methylation is unsure in vivo.

Similarity. Belongs to the Antp homeobox family. IPF1/XlHbox-8 subfamily.

RefSeq proteins (1): NP_000200* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR017970	Homeobox_CS	Conserved_site
IPR017995	Homeobox_antennapedia	Family
IPR020479	HD_metazoa	Domain

Pfam: PF00046

UniProt features (20 total): sequence variant 5, sequence conflict 3, region of interest 3, compositionally biased region 3, modified residue 2, short sequence motif 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7KPK	X-RAY DIFFRACTION	1.71
6F8F	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52945-F1	65.99	0.22

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 151, 268

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-210745	Regulation of gene expression in beta cells
R-HSA-210747	Regulation of gene expression in early pancreatic precursor cells
R-HSA-9925561	Developmental Lineage of Pancreatic Acinar Cells
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells
R-HSA-9937080	Developmental Lineage of Multipotent Pancreatic Progenitor Cells

MSigDB gene sets: 364 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_EPITHELIAL_CELL_APOPTOTIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, PID_HNF3B_PATHWAY, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_RESPONSE_TO_PEPTIDE, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION

GO Biological Process (56): negative regulation of transcription by RNA polymerase II (GO:0000122), liver development (GO:0001889), type B pancreatic cell differentiation (GO:0003309), glucose metabolic process (GO:0006006), generation of precursor metabolites and energy (GO:0006091), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), smoothened signaling pathway (GO:0007224), response to xenobiotic stimulus (GO:0009410), animal organ morphogenesis (GO:0009887), response to iron(II) ion (GO:0010040), response to chlorate (GO:0010157), glucose mediated signaling pathway (GO:0010255), morphogenesis of embryonic epithelium (GO:0016331), insulin secretion (GO:0030073), exocrine pancreas development (GO:0031017), animal organ regeneration (GO:0031100), positive regulation of insulin secretion (GO:0032024), response to vitamin (GO:0033273), response to cytokine (GO:0034097), response to nicotine (GO:0035094), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), response to L-leucine (GO:0043201), response to alkaloid (GO:0043279), type B pancreatic cell proliferation (GO:0044342), positive regulation of transcription by RNA polymerase II (GO:0045944), digestive tract development (GO:0048565), stem cell differentiation (GO:0048863), negative regulation of epithelial cell proliferation (GO:0050680), response to glucocorticoid (GO:0051384), transdifferentiation (GO:0060290), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), response to fatty acid (GO:0070542), type B pancreatic cell apoptotic process (GO:0097050), negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway (GO:1902236), cellular response to acadesine (GO:1904102), positive regulation of type B pancreatic cell proliferation (GO:1904692), negative regulation of type B pancreatic cell apoptotic process (GO:2000675), DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (11): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), protein-containing complex binding (GO:0044877), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), sequence-specific double-stranded DNA binding (GO:1990837), promoter-specific chromatin binding (GO:1990841), DNA binding (GO:0003677), chromatin binding (GO:0003682), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), nuclear speck (GO:0016607), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Developmental Cell Lineages of the Exocrine Pancreas	3
Regulation of beta-cell development	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
gland development	2
regulation of DNA-templated transcription	2
animal organ development	2
binding	2
negative regulation of DNA-templated transcription	1
hepaticobiliary system development	1
endocrine pancreas development	1
enteroendocrine cell differentiation	1
hexose metabolic process	1
metabolic process	1
DNA-templated transcription	1
cell surface receptor signaling pathway	1
response to chemical	1
anatomical structure morphogenesis	1
response to iron ion	1
response to oxygen-containing compound	1
hexose mediated signaling	1
cellular response to glucose stimulus	1
morphogenesis of an epithelium	1
embryonic morphogenesis	1
protein secretion	1
peptide hormone secretion	1
pancreas development	1
exocrine system development	1
digestive system development	1
regeneration	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
response to nutrient	1
response to peptide	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1

Protein interactions and networks

STRING

1170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDX1	PBX1	P40424	873
PDX1	GCK	P35557	868
PDX1	NEUROG3	Q9Y4Z2	868
PDX1	FOXA2	Q9Y261	866
PDX1	INS	P01308	853
PDX1	PTF1A	Q7RTS3	851
PDX1	HNF1A	P20823	828
PDX1	NEUROD1	Q13562	813
PDX1	GCG	P01275	808
PDX1	HNF1B	P35680	798
PDX1	SST	P01166	731
PDX1	MAFA	Q8NHW3	725
PDX1	ONECUT1	Q9UBC0	720
PDX1	RFX6	Q8HWS3	714
PDX1	KCNJ11	Q14654	704

IntAct

6 interactions, top by confidence:

A	B	Type	Score
PDX1	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
PDX1	PASK	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
NAV3	CUX2	psi-mi:“MI:0914”(association)	0.350
PDX1	HIRA	psi-mi:“MI:0914”(association)	0.350
	PIK3R2	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): MAPK14 (Affinity Capture-Western), PCIF1 (Affinity Capture-Western), PCIF1 (Co-localization), PCIF1 (Reconstituted Complex), PDX1 (Affinity Capture-Western), PDX1 (Reconstituted Complex), PDX1 (Co-crystal Structure), SPOP (Reconstituted Complex), SPOP (Protein-peptide), ERBB2IP (Affinity Capture-MS), PDX1 (Affinity Capture-MS), VPS9D1 (Affinity Capture-MS), HIRA (Affinity Capture-MS), PDX1 (Co-crystal Structure), PDX1 (Reconstituted Complex)

ESM2 similar proteins: A1YER7, A1YF08, A1YFD8, A1YFY3, A1YG01, A1YG85, A2D4P8, A2D4R4, A2D5I1, A2D649, A2T6H5, A2T6X6, A2T6Z0, A2T748, A2T756, A2T7H5, A2T7J2, P06798, P09016, P09017, P09023, P09024, P10284, P10628, P13378, P14653, P17277, P17483, P17509, P18111, P18864, P23463, P23813, P31259, P31275, P31276, P31277, P31310, P47902, P50207

Diamond homologs: A0JPN1, A1YG85, A5PKG8, A6NJ46, A6NMT0, A7MB54, A9L937, B0VXK3, D2KQB0, E7FDX5, M0R6D8, O08686, O13023, O35762, O42365, O43364, O43711, O55144, O88181, O93366, O93367, O93590, P0C1T1, P10035, P14652, P14837, P20009, P28468, P31245, P31246, P31261, P31314, P42583, P42584, P43120, P43345, P43688, P50219, P52945, P52950

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
MAFA	“up-regulates quantity by expression”	PDX1	“transcriptional regulation”
PDX1	“up-regulates quantity by expression”	GCK	“transcriptional regulation”
PDX1	“up-regulates quantity by expression”	Hexokinase	“transcriptional regulation”
STK4	“down-regulates activity”	PDX1	phosphorylation
XRCC5	“down-regulates quantity by destabilization”	PDX1	binding
PRKDC	“down-regulates quantity by destabilization”	PDX1	phosphorylation
HIPK2	unknown	PDX1	phosphorylation
PDX1	“up-regulates quantity by expression”	SLC2A2	“transcriptional regulation”
PDX1	“up-regulates quantity by expression”	INS	“transcriptional regulation”
PDX1	“up-regulates quantity by expression”	NKX6-1	“transcriptional regulation”
GSK3B	“down-regulates quantity”	PDX1	phosphorylation
SPOP	“down-regulates quantity”	PDX1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

262 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	10
Uncertain significance	147
Likely benign	58
Benign	9

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
30124	NM_000209.4(PDX1):c.533A>G (p.Glu178Gly)	Pathogenic
3902578	NM_000209.4(PDX1):c.494_497delinsAC (p.Phe165fs)	Pathogenic
8865	NM_000209.4(PDX1):c.532G>A (p.Glu178Lys)	Pathogenic
1755049	NM_000209.4(PDX1):c.671_672dup (p.Gln225fs)	Likely pathogenic
2505338	NM_000209.4(PDX1):c.735dup (p.Gly246fs)	Likely pathogenic
2506152	NM_000209.4(PDX1):c.488A>G (p.Lys163Arg)	Likely pathogenic
2635693	NM_000209.4(PDX1):c.653del (p.Gly218fs)	Likely pathogenic
36407	NM_000209.4(PDX1):c.442C>G (p.Arg148Gly)	Likely pathogenic
36409	NM_000209.4(PDX1):c.571A>C (p.Lys191Gln)	Likely pathogenic
3906449	NM_000209.4(PDX1):c.54C>A (p.Cys18Ter)	Likely pathogenic
436282	NM_000209.4(PDX1):c.502A>C (p.Asn168His)	Likely pathogenic
4526486	NM_000209.4(PDX1):c.533A>C (p.Glu178Ala)	Likely pathogenic
804928	NM_000209.4(PDX1):c.683_699del (p.Ala228fs)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1804 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:27920499:T:A	W121R	1.000
13:27920499:T:C	W121R	1.000
13:27920503:T:C	M122T	1.000
13:27924297:C:A	R150S	1.000
13:27924297:C:G	R150G	1.000
13:27924297:C:T	R150C	1.000
13:27924304:C:A	A152D	1.000
13:27924306:T:A	Y153N	1.000
13:27924306:T:C	Y153H	1.000
13:27924306:T:G	Y153D	1.000
13:27924307:A:G	Y153C	1.000
13:27924320:G:C	Q157H	1.000
13:27924320:G:T	Q157H	1.000
13:27924322:T:C	L158P	1.000
13:27924325:T:C	L159P	1.000
13:27924331:T:A	L161Q	1.000
13:27924331:T:C	L161P	1.000
13:27924331:T:G	L161R	1.000
13:27924333:G:A	E162K	1.000
13:27924334:A:C	E162A	1.000
13:27924334:A:T	E162V	1.000
13:27924335:G:C	E162D	1.000
13:27924335:G:T	E162D	1.000
13:27924339:G:A	E164K	1.000
13:27924341:G:C	E164D	1.000
13:27924341:G:T	E164D	1.000
13:27924342:T:A	F165I	1.000
13:27924342:T:C	F165L	1.000
13:27924342:T:G	F165V	1.000
13:27924343:T:C	F165S	1.000

dbSNP variants (sampled 300 via entrez): RS1000161787 (13:27918271 C>T), RS1000381183 (13:27920747 C>G,T), RS1000743478 (13:27919345 A>G,T), RS1000849832 (13:27919917 C>T), RS1000923448 (13:27920081 G>GCTCCCGA), RS1001135445 (13:27924826 C>A,G,T), RS1001153429 (13:27925615 TCTC>T,TCTCCTC), RS1001682883 (13:27921454 G>T), RS1001854483 (13:27918573 G>A), RS1001928024 (13:27918952 G>A), RS1002026150 (13:27920272 C>G,T), RS1002205898 (13:27923851 G>T), RS1002689107 (13:27922584 C>A,G), RS1003231977 (13:27926604 T>C), RS1003265239 (13:27921149 A>C)

Disease associations

OMIM: gene MIM:600733 | disease phenotypes: MIM:125853, MIM:606392, MIM:125850, MIM:606391, MIM:260370, MIM:606176

GenCC curated gene-disease

Disease	Classification	Inheritance
maturity-onset diabetes of the young type 4	Definitive	Autosomal dominant
pancreatic agenesis 1	Strong	Autosomal recessive
permanent neonatal diabetes mellitus	Strong	Autosomal recessive
pancreatic agenesis	Supportive	Autosomal recessive
maturity-onset diabetes of the young	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
monogenic diabetes	Moderate	AD
pancreatic agenesis 1	Definitive	AR

Mondo (8): type 2 diabetes mellitus (MONDO:0005148), maturity-onset diabetes of the young type 4 (MONDO:0011667), maturity-onset diabetes of the young (MONDO:0018911), pancreatic agenesis 1 (MONDO:0024547), monogenic diabetes (MONDO:0015967), permanent neonatal diabetes mellitus (MONDO:0100164), neonatal diabetes mellitus (MONDO:0016391), pancreatic agenesis (MONDO:0009832)

Orphanet (5): Partial pancreatic agenesis (Orphanet:2805), MODY (Orphanet:552), Rare genetic diabetes mellitus (Orphanet:183625), Isolated permanent neonatal diabetes mellitus (Orphanet:99885), Neonatal diabetes mellitus (Orphanet:224)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0004904	Maturity-onset diabetes of the young

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
C563425	Diabetes Mellitus, Permanent Neonatal (supp.)
C562772	Mason-Type Diabetes (supp.)
C563451	Maturity-Onset Diabetes of the Young, Type 4 (supp.)
C564908	Pancreatic Agenesis, Congenital (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Glucose	increases activity, increases phosphorylation, affects cotreatment, affects localization, decreases reaction	3
sodium arsenite	affects localization, decreases reaction, increases activity, increases phosphorylation, affects cotreatment	2
SB 203580	affects localization, decreases reaction, increases activity, increases phosphorylation, affects cotreatment	2
Wortmannin	affects cotreatment, affects localization, decreases reaction, increases activity, increases phosphorylation	2
Benzo(a)pyrene	affects methylation, increases expression	2
Palmitic Acid	affects localization, decreases reaction, decreases expression	2
bisphenol A	affects cotreatment, increases methylation	1
terbufos	increases methylation	1
arsenite	increases methylation	1
mono-(2-ethylhexyl)phthalate	increases expression	1
monobutyl phthalate	increases expression	1
calyculin A	affects localization, decreases reaction	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects localization, decreases reaction, increases activity, increases phosphorylation	1
6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide	decreases reaction, increases expression, increases reaction	1
imeglimin	increases expression	1
Resveratrol	increases reaction, decreases reaction, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Amiloride	decreases uptake	1
Arsenicals	decreases methylation	1
Fonofos	increases methylation	1
Harmine	increases expression	1
Parathion	increases methylation	1
Cytochalasin D	decreases uptake	1
Okadaic Acid	affects localization, decreases reaction	1

Cellosaurus cell lines

9 cell lines: 3 embryonic stem cell, 2 induced pluripotent stem cell, 2 cancer cell line, 1 transformed cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0562	TRM-6/PDX-1	Transformed cell line	Sex unspecified
CVCL_A4MW	PDX1 P33T iPSC1	Induced pluripotent stem cell	Female
CVCL_A4MX	PDX1 C18R iPSC1	Induced pluripotent stem cell	Female
CVCL_A5G8	SEES3-1V human PDX1, clone1	Embryonic stem cell	Male
CVCL_A5G9	SEES3-1V human PDX1, clone2	Embryonic stem cell	Male
CVCL_A5H0	SEES3-1V human PDX1, clone3	Embryonic stem cell	Male
CVCL_D1Y7	Abcam A-549 PDX1 KO	Cancer cell line	Male
CVCL_D6B5	HyCyte DLD-1 KO-hPDX1	Cancer cell line	Male
CVCL_LB87	NISK9	Spontaneously immortalized cell line

Clinical trials (associated diseases)

319 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02624817	PHASE4	COMPLETED	Long-Term Sulfonylurea Response in KCNJ11 Neonatal Diabetes
NCT02624830	PHASE4	UNKNOWN	Long-Term Sulfonylurea Response in ABCC8 Neonatal Diabetes (SuResponsSUR)
NCT00006163	PHASE4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	PHASE4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	PHASE4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	PHASE4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	PHASE4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	PHASE4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	PHASE4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	PHASE4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	PHASE4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	PHASE4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	PHASE4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	PHASE4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	PHASE4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	PHASE4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	PHASE4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	PHASE4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	PHASE4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	PHASE4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	PHASE4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	PHASE4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	PHASE4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	PHASE4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	PHASE4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	PHASE4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	PHASE4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	PHASE4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	PHASE4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	PHASE4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	PHASE4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	PHASE4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	PHASE4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	PHASE4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes