PDCD6

Summary

PDCD6 (programmed cell death 6, HGNC:8765) is a protein-coding gene on chromosome 5p15.33, encoding Programmed cell death protein 6 (O75340). Calcium sensor that plays a key role in processes such as endoplasmic reticulum (ER)-Golgi vesicular transport, endosomal biogenesis or membrane repair. It is a selective cancer dependency (DepMap: 23.3% of cell lines).

This gene encodes a calcium-binding protein belonging to the penta-EF-hand protein family. Calcium binding is important for homodimerization and for conformational changes required for binding to other protein partners. This gene product participates in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death. In mice deficient for this gene product, however, apoptosis was not blocked suggesting this gene product is functionally redundant. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is also located on the short arm of chromosome 5.

Source: NCBI Gene 10016 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 31 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 23.3% of screened cell lines
• MANE Select transcript: NM_013232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8765
Approved symbol	PDCD6
Name	programmed cell death 6
Location	5p15.33
Locus type	gene with protein product
Status	Approved
Aliases	ALG-2, PEF1B
Ensembl gene	ENSG00000249915
Ensembl biotype	protein_coding
OMIM	601057
Entrez	10016

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000264933, ENST00000505221, ENST00000505526, ENST00000507473, ENST00000507528, ENST00000509581, ENST00000511482, ENST00000512466, ENST00000513582, ENST00000515587, ENST00000614778, ENST00000618970, ENST00000874098

RefSeq mRNA: 5 — MANE Select: NM_013232 NM_001267556, NM_001267557, NM_001267558, NM_001267559, NM_013232

CCDS: CCDS3854, CCDS58940, CCDS58941, CCDS75222, CCDS75223

Canonical transcript exons

ENST00000264933 — 6 exons

Exon	Start	End
ENSE00003351398	314417	314974
ENSE00003479418	306602	306760
ENSE00003665937	311293	311402
ENSE00003848423	271646	271821
ENSE00003849491	304177	304221
ENSE00003849790	272711	272772

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 98.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.4025 / max 50.0363, expressed in 1738 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55463	82.9489	1825
55462	7.2950	1736
55461	0.1074	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.83	gold quality
stromal cell of endometrium	CL:0002255	98.02	gold quality
mucosa of transverse colon	UBERON:0004991	97.92	gold quality
esophagus mucosa	UBERON:0002469	97.79	gold quality
right adrenal gland cortex	UBERON:0035827	97.74	gold quality
right adrenal gland	UBERON:0001233	97.73	gold quality
prefrontal cortex	UBERON:0000451	97.56	gold quality
left adrenal gland	UBERON:0001234	97.56	gold quality
left adrenal gland cortex	UBERON:0035825	97.52	gold quality
rectum	UBERON:0001052	97.51	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.31	gold quality
adenohypophysis	UBERON:0002196	97.29	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.27	gold quality
adrenal gland	UBERON:0002369	97.24	gold quality
frontal cortex	UBERON:0001870	97.21	gold quality
cerebral cortex	UBERON:0000956	97.17	gold quality
pituitary gland	UBERON:0000007	97.16	gold quality
Ammon’s horn	UBERON:0001954	97.14	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.13	gold quality
metanephros cortex	UBERON:0010533	97.09	gold quality
superior frontal gyrus	UBERON:0002661	97.08	gold quality
vagina	UBERON:0000996	97.04	gold quality
anterior cingulate cortex	UBERON:0009835	97.02	gold quality
left lobe of thyroid gland	UBERON:0001120	96.99	gold quality
hypothalamus	UBERON:0001898	96.99	gold quality
putamen	UBERON:0001874	96.98	gold quality
brain	UBERON:0000955	96.97	gold quality
caudate nucleus	UBERON:0001873	96.97	gold quality
right lobe of thyroid gland	UBERON:0001119	96.96	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.83

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

39 targeting PDCD6, 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-548N	99.98	71.94	4170
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-5690	99.25	67.58	1012
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 23.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Apoptosis-linked gene 2 binds to the death domain of Fas and dissociates from Fas during Fas-mediated apoptosis in Jurkat cells. (PMID:11606059)
• ALG-2 is stabilized by dimerization through its fifth EF-hand region (PMID:11883899)
• Pro/Gly/Tyr/Ala-rich hydrophobic region in Anexin XI masked the Ca(2+)-dependently exposed hydrophobic surface of ALG-2. (PMID:11883939)
• The penta-EF-hand domain of ALG-2 interacts with amino-terminal domains of both annexin VII and annexin XI in a Ca2+-dependent manner. (PMID:12445460)
• ALG-2 has roles in both cell proliferation and cell death. (PMID:12445461)
• Data show that ALG-2 is overexpressed in liver and lung neoplasms, and is mainly found in epithelial cells in the lung. (PMID:12819013)
• The down-regulation of ALG-2 in human uveal melanoma cells compared to their progenitor cells, normal melanocytes, may provide melanoma cells with a selective advantage by interfering with Ca+-mediated apoptotic signals, thereby enhancing cell survival. (PMID:15366927)
• Raf-1 may mediate its anti-apoptotic function by interrupting ASK1-dependent phosphorylation of ALG-2. (PMID:15925322)
• ALG-2 is recruited to endoplasmic reticulum exit sites via Ca(2+)-dependent interaction with Sec31A and in turn stabilizes the localization of Sec31A at these sites. (PMID:16957052)
• ALG-2 alone evenly distributed within the cell, whereas in the presence of RBM22 the two proteins co-localized within the nucleus. (PMID:17045351)
• These findings establish Sec31A as a novel target for ALG-2 and provide a framework for studies on the roles of ALG-2 in ER-Golgi transport. (PMID:17196169)
• ALG-2 binding to Scotin is strictly calcium dependent, indicating a role of this interaction in calcium signaling pathways (PMID:17889823)
• Identification of Alix-type and Non-Alix-type ALG-2-binding sites in human phospholipid scramblase 3: differential binding to an alternatively spliced isoform and amino acid-substituted mutants (PMID:18256029)
• Alix and ALG-2 are new actors of the TNF-R1 pathway (PMID:18936101)
• A Ca(2+)/EF3-driven arginine switch mechanism for ALG-2 binding to Alix. (PMID:18940611)
• lower mRNA expression levels of PDCD6 were correlated significantly with a poor overall survival in gastric cancer. (PMID:18957060)
• Results describe the crystallization and structural analysis of N-terminally truncated human ALG-2. (PMID:18997320)
• These results indicate that ALG-2 has an anti-apoptotic function in HeLa cells by facilitating the passage through checkpoints in the G2/M cell cycle phase. (PMID:19013425)
• analysed the expression of ALG-2 in 7371 tumor tissue samples of various origin; most notably, ALG-2 was upregulated in mesenchymal tumors. (PMID:19383317)
• Ca2+-loaded ALG-2 bridges Alix and TSG101 as an adaptor protein. (PMID:19520058)
• ALG-2 acts as a Ca(2+) sensor that modulates the function of MCOLN1 along the late endosomal-lysosomal pathway. (PMID:19864416)
• found that targeting Requiem and Alg-2 did not result in extended culture viability, but resulted in an increase in maximum viable cell numbers and cumulative IVCD under fed-batch conditions (PMID:20571937)
• inability of the two-residue shorter ALG-2 isoform to bind Alix (PMID:20691033)
• the alg2 binding site is one of the key determinants of the retention kinetics of Sec31A at endoplasmic reticulum exit sites (PMID:20834162)
• programmed cell death 6 protein plays a significant role in modulating cellular angiogenesis (PMID:21893193)
• PDCD6 exerts its anti-tumor potency by activating the p53-p21 protein for G1 phase of cell cycle progression and apoptosis (PMID:22142513)
• PDCD6 may have a role in advanced gastric cancer (PMID:22161137)
• PDCD6 seems to play an important role in ovarian cancer progression. (PMID:22369209)
• This is the first report showing interaction of ALG-2 with a P-body component (PATL1).PATL1 as well as DCP1A, a well-known P-body marker, co-localized with a subset of ALG-2. (PMID:22437941)
• we conclude that a novel p53-responsive gene PDCD6 is accumulated in the nucleus and induces apoptosis in response to DNA damage. (PMID:22712728)
• the current study indicates that PDCD6 gene may be a new susceptibility gene to endometriosis. (PMID:23137875)
• The results of this study show that rs4957014G/T is associated with an increased risk of non-small cell lung cancer (NSCLC), which suggest that PDCD6 gene single nucleotide polymorphism is a risk factor for susceptibility of NSCLC. (PMID:23167403)
• Palmitoylation sites and the N-terminal Pro-rich region were necessary for efficient secretion, but ABSs (ALG-2-binding sites) were dispensable. (PMID:23350699)
• The present study provided evidence that rs4957014 and rs3756712 are associated with Uterine leiomyoma (UL) risk, the results indicated that genetic polymorphisms in PDCD6 may contribute to the development of UL. (PMID:23551056)
• the binding of ALG-2 to IST1 is Ca(2+)-dependent (PMID:23649269)
• The results of in vitro binding assays using purified recombinant proteins indicated that ALG-2 functions as a Ca(2)-dependent adaptor protein that bridges ALIX and ESCRT-I to form a ternary complex (PMID:23924735)
• ALG-2 attenuates COPII budding in vitro and stabilizes the Sec23/Sec31A complex. (PMID:24069399)
• CHERP and ALG-2 participate in regulation of alternative splicing of IP3R1 pre-mRNA and provide new insights into post-transcriptional regulation of splicing variants in Ca(2+) signaling pathways. (PMID:24078636)
• PDCD6 may represent a biomarker candidate gene that could help to identify a group of patients at high risk for recurrence and death. (PMID:24792888)
• ALG-2/Sec31A interactions were not required for the localization of Sec31A to ER exit sites per se but appeared to acutely regulate the stability and trafficking of the cargo receptor p24 and the distribution of the vesicle tether protein p115 (PMID:25006245)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdcd6	ENSDARG00000005220
mus_musculus	Pdcd6	ENSMUSG00000021576
rattus_norvegicus	Pdcd6	ENSRNOG00000014485
drosophila_melanogaster	Alg-2	FBGN0086378
caenorhabditis_elegans	M04F3.4	WBGENE00019770

Paralogs (20): CAPN1 (ENSG00000014216), SRI (ENSG00000075142), CAPN6 (ENSG00000077274), CAPN3 (ENSG00000092529), CAPN15 (ENSG00000103326), GCA (ENSG00000115271), ADGB (ENSG00000118492), CAPNS1 (ENSG00000126247), CAPN7 (ENSG00000131375), CAPN9 (ENSG00000135773), CAPN11 (ENSG00000137225), CAPN10 (ENSG00000142330), CAPN5 (ENSG00000149260), PEF1 (ENSG00000162517), CAPN2 (ENSG00000162909), CAPN13 (ENSG00000162949), CAPN12 (ENSG00000182472), CAPN8 (ENSG00000203697), CAPN14 (ENSG00000214711), CAPNS2 (ENSG00000256812)

Protein

Protein identifiers

Programmed cell death protein 6 — O75340 (reviewed: O75340)

Alternative names: Apoptosis-linked gene 2 protein homolog

All UniProt accessions (6): A0A024QZ42, A0A087WZ38, D6RA21, O75340, H0Y9X3, Q86W51

UniProt curated annotations — full annotation on UniProt →

Function. Calcium sensor that plays a key role in processes such as endoplasmic reticulum (ER)-Golgi vesicular transport, endosomal biogenesis or membrane repair. Acts as an adapter that bridges unrelated proteins or stabilizes weak protein-protein complexes in response to calcium: calcium-binding triggers exposure of apolar surface, promoting interaction with different sets of proteins thanks to 3 different hydrophobic pockets, leading to translocation to membranes. Involved in ER-Golgi transport by promoting the association between PDCD6IP and TSG101, thereby bridging together the ESCRT-III and ESCRT-I complexes. Together with PEF1, acts as a calcium-dependent adapter for the BCR(KLHL12) complex, a complex involved in ER-Golgi transport by regulating the size of COPII coats. In response to cytosolic calcium increase, the heterodimer formed with PEF1 interacts with, and bridges together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export, which is required for neural crest specification. Involved in the regulation of the distribution and function of MCOLN1 in the endosomal pathway. Promotes localization and polymerization of TFG at endoplasmic reticulum exit site. Required for T-cell receptor-, Fas-, and glucocorticoid-induced apoptosis. May mediate Ca(2+)-regulated signals along the death pathway: interaction with DAPK1 can accelerate apoptotic cell death by increasing caspase-3 activity. Its role in apoptosis may however be indirect, as suggested by knockout experiments. May inhibit KDR/VEGFR2-dependent angiogenesis; the function involves inhibition of VEGF-induced phosphorylation of the Akt signaling pathway. In case of infection by HIV-1 virus, indirectly inhibits HIV-1 production by affecting viral Gag expression and distribution. Has a lower Ca(2+) affinity than isoform 1.

Subunit / interactions. Homodimer and heterodimer; heterodimerizes (via the EF-hand 5) with PEF1. Isoform 1 and isoform 2 self-associate; probably forming homodimers. Interacts with CPNE4 (via VWFA domain). Interacts with PDCD6IP; the interaction is calcium-dependent. Interacts with RBM22. Interacts with PLSCR4. Interacts with ANXA7 and TSG101. Interacts with DAPK1. Interacts with SEC31A; the interaction is calcium-dependent and promotes monoubiquitination of SEC31A. Interacts with ANXA11 (via N-terminus); the interaction is calcium-dependent. Interacts with PLSCR3 (via N-terminus); the interaction is calcium-dependent. Interacts with MCOLN1; the interaction is calcium-dependent. Interacts with KDR; the interaction is calcium-dependent. Interacts with HEBP2; the interaction is calcium-dependent. Interacts with TFG. Isoform 1: Interacts with SHISA5, leading to stabilize it. Isoform 2: Does not interact with SHISA5. Isoform 2: Does not interact with PDCD6IP, TSG101, ANXA7 and ANXA11.

Subcellular location. Endoplasmic reticulum membrane. Cytoplasmic vesicle. COPII-coated vesicle membrane. Cytoplasm. Nucleus. Endosome.

Domain organisation. Interacts with different set of proteins thanks to 3 different hydrophobic pockets. Hydrophobic pockets 1 and 2, which mediate interaction with PDCD6IP, are largely formed by residues from EF-hand 3 (EF3) to 5 (EF5), as well as by Tyr-180 (EF5) of a dimerizing molecule (Pocket 1) and from EF-hand (EF2) to 4 (EF4) (Pocket 2). Hydrophobic pocket 3, which mediates interaction with SEC31A, is mainly formed by residues from EF-hand 1 (EF1) to 3 (EF3). EF-hand 1 (EF1) and 3 (EF3) are the high-affinity calcium-binding sites, while EF-hand 5 (EF5) binds calcium with low-affinity. A one-residue insertion in the EF5-binding loop prevents the glutamyl residue at the C-terminal end of the loop from serving as the canonical bidentate calcium ligand. EF5 acts as a high-affinity magnesium-binding domain instead. Magnesium, may affect dimerization. EF5 may bind either calcium or magnesium depending on the context.

Isoforms (3)

UniProt ID	Names	Canonical?
O75340-1	1	yes
O75340-2	2, ALG-2(delta)GF122
O75340-3	3

RefSeq proteins (5): NP_001254485, NP_001254486, NP_001254487, NP_001254488, NP_037364* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR051426	Peflin/Sorcin_CaBP	Family

Pfam: PF13499

UniProt features (57 total): mutagenesis site 17, binding site 14, helix 8, strand 7, domain 5, splice variant 2, initiator methionine 1, chain 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
2ZND	X-RAY DIFFRACTION	1.7
2ZNE	X-RAY DIFFRACTION	2.2
5GQQ	X-RAY DIFFRACTION	2.2
3WXA	X-RAY DIFFRACTION	2.36
2ZN9	X-RAY DIFFRACTION	2.4
3AAJ	X-RAY DIFFRACTION	2.4
2ZN8	X-RAY DIFFRACTION	2.7
3AAK	X-RAY DIFFRACTION	2.7
2ZRS	X-RAY DIFFRACTION	3.1
2ZRT	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75340-F1	90.08	0.83

Functional residue map

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

Ligand- & substrate-binding residues (14): 42; 47; 103; 105; 107; 109; 114; 169; 171; 173; 175; 36 …

Post-translational modifications (1): 2

Mutagenesis-validated functional residues (17):

Position	Phenotype
47	loss of interaction with sec31a and plscr3, and loss of localization to the endoplasmic reticulum; when associated with
52	strongly impaired interaction with sec31a. slightly reduced interaction with pdcd6ip.
53	slightly reduced interaction with sec31a. does not affect interaction with pdcd6ip.
57	does not affect interaction with sec31a. reduces the interaction with hebp2, pdcd6ip and anxa7.
60	abolishes the interaction with sec31a, pdcd6ip, anxa7 and anxa11.
85	strongly impaired interaction with sec31a and tfg. does not affect interaction with pdcd6ip.
89	does not affect interaction with sec31a. does not affect interaction with pdcd6ip.
91	abolishes the interaction with pdcd6ip, anxa7 and anxa11.
92	does not affect interaction with sec31a. does not affect interaction with pdcd6ip.
95	abolishes the interaction with pdcd6ip, anxa7 and anxa11.
114	loss of interaction with sec31a and plscr3, and loss of localization to the endoplasmic reticulum; when associated with
122	increases interaction with pdcd6ip and anxa7. impairs interaction with anxa11. augments stauroporine-induced cell death.
122	increases interaction with pdcd6ip. impairs interaction with anxa11.
122	increases interaction with pdcd6ip. impairs interaction with anax7 and anxa11.
122	impairs interaction with anxa11.
148	slightly reduced interaction with sec31a. does not affect interaction with pdcd6ip.
180	abolishes the interaction with pdcd6ip, tsg101, anxa7 and anxa11. does not affect interaction with tfg and sec31a.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 316 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, AAGCAAT_MIR137, MORF_MBD4, MORF_RAB5A, GOBP_VESICLE_LOCALIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, MODULE_255, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_VESICLE_ORGANIZATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, MORF_RAD21, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (19): angiogenesis (GO:0001525), positive regulation of endothelial cell proliferation (GO:0001938), intracellular protein transport (GO:0006886), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), positive regulation of endothelial cell migration (GO:0010595), neural crest formation (GO:0014029), neural crest cell development (GO:0014032), negative regulation of vascular endothelial growth factor receptor signaling pathway (GO:0030948), negative regulation of TOR signaling (GO:0032007), cellular response to heat (GO:0034605), vascular endothelial growth factor receptor-2 signaling pathway (GO:0036324), positive regulation of apoptotic process (GO:0043065), positive regulation of angiogenesis (GO:0045766), COPII vesicle coat assembly (GO:0048208), response to calcium ion (GO:0051592), negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051898), apoptotic signaling pathway (GO:0097190), positive regulation of protein monoubiquitination (GO:1902527), apoptotic process (GO:0006915)

GO Molecular Function (12): magnesium ion binding (GO:0000287), calcium ion binding (GO:0005509), protein-macromolecule adaptor activity (GO:0030674), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein-membrane adaptor activity (GO:0043495), protein heterodimerization activity (GO:0046982), protein dimerization activity (GO:0046983), calcium-dependent protein binding (GO:0048306), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (15): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), COPII vesicle coat (GO:0030127), cytoplasmic vesicle (GO:0031410), Cul3-RING ubiquitin ligase complex (GO:0031463), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), endoplasmic reticulum exit site (GO:0070971), ER to Golgi transport vesicle membrane (GO:0012507), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasm	5
protein binding	4
anatomical structure formation involved in morphogenesis	2
intracellular transport	2
vascular endothelial growth factor receptor signaling pathway	2
negative regulation of intracellular signal transduction	2
apoptotic process	2
metal ion binding	2
protein dimerization activity	2
intracellular membrane-bounded organelle	2
endomembrane system	2
blood vessel morphogenesis	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
intracellular protein localization	1
protein transport	1
intercellular transport	1
Golgi vesicle transport	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
endothelial cell migration	1
epithelial to mesenchymal transition	1
chordate embryonic development	1
neural crest cell differentiation	1
stem cell development	1
negative regulation of signal transduction	1
regulation of vascular endothelial growth factor receptor signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
TOR signaling	1
regulation of TOR signaling	1
response to heat	1
cellular response to stress	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
vesicle coat assembly	1

Protein interactions and networks

STRING

1378 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDCD6	PDCD6IP	Q8WUM4	998
PDCD6	TSG101	Q99816	981
PDCD6	VPS4B	O75351	851
PDCD6	CHMP4A	Q9BY43	843
PDCD6	SEC31A	O94979	820
PDCD6	CEP55	Q53EZ4	792
PDCD6	ALG1	Q9BT22	777
PDCD6	MCOLN1	Q9GZU1	777
PDCD6	ALG6	Q9Y672	763
PDCD6	CHMP4C	Q96CF2	745
PDCD6	VPS4A	Q9UN37	663
PDCD6	PLTP	P55058	648
PDCD6	SH3GL1	Q99961	535
PDCD6	SH3GL3	Q99963	524
PDCD6	SDCBP	O00560	523

IntAct

190 interactions, top by confidence:

A	B	Type	Score
PEF1	PDCD6	psi-mi:“MI:0915”(physical association)	0.900
PDCD6	PEF1	psi-mi:“MI:0915”(physical association)	0.900
PDCD6IP	PDCD6	psi-mi:“MI:0914”(association)	0.900
PDCD6	PDCD6IP	psi-mi:“MI:0407”(direct interaction)	0.900
PDCD6	PDCD6IP	psi-mi:“MI:0915”(physical association)	0.900
PDCD6IP	PDCD6	psi-mi:“MI:0915”(physical association)	0.900
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
PEF1	PDCD6	psi-mi:“MI:0914”(association)	0.900
HEBP2	PDCD6	psi-mi:“MI:0915”(physical association)	0.840
PDCD6	HEBP2	psi-mi:“MI:0915”(physical association)	0.840
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
PDCD6	PDCD6	psi-mi:“MI:0915”(physical association)	0.760
PDCD6	PDCD6	psi-mi:“MI:0407”(direct interaction)	0.760

BioGRID (308): DAPK1 (Two-hybrid), DAPK1 (Affinity Capture-Western), PDCD6 (Two-hybrid), PDCD6 (Two-hybrid), HEBP2 (Two-hybrid), VPS37C (Two-hybrid), PEF1 (Two-hybrid), PDCD6 (Affinity Capture-RNA), PDCD6 (Affinity Capture-RNA), HEBP2 (Two-hybrid), MAPK1IP1L (Two-hybrid), PDCD6 (Two-hybrid), HNRNPU (Co-fractionation), HNRNPUL1 (Co-fractionation), HNRNPUL2 (Co-fractionation)

ESM2 similar proteins: A4IF97, F1SSF9, G3V7W1, O14950, O75340, P02608, P02609, P04466, P06815, P07461, P08733, P10916, P12815, P18666, P19105, P24732, P28676, P40423, P41691, P43367, P51667, P97457, Q01449, Q09510, Q0P571, Q0VFG3, Q27179, Q2QY10, Q3SEK0, Q3SZE5, Q3THE2, Q5E9E2, Q5PQ53, Q5RC34, Q5XJX1, Q63ZJ3, Q64122, Q641Z8, Q6DC93, Q7F0J0

Diamond homologs: A6NHC0, G3V7W1, O75340, O88456, P02627, P04574, P04632, P05044, P06704, P06813, P07290, P07291, P12815, P13135, P28676, P30626, P42322, P48451, Q06BI3, Q12798, Q1PFH8, Q24214, Q2QY10, Q38868, Q39584, Q5PQ53, Q5R4U9, Q5RAI6, Q641Z8, Q64537, Q6DC93, Q6F334, Q6P069, Q8BFY6, Q8VC88, Q8W4L0, Q94743, Q95YL5, Q96L46, Q9BXU9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 135 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cellular responses to stress	10	4.6×	8e-03
Cellular responses to stimuli	11	4.3×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
G1/S transition of mitotic cell cycle	7	13.8×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2087 predictions. Top by Δscore:

Variant	Effect	Δscore
5:279092:G:T	donor_gain	1.0000
5:306594:T:TA	acceptor_gain	1.0000
5:306597:CTCA:C	acceptor_loss	1.0000
5:306599:CAGC:C	acceptor_loss	1.0000
5:306600:A:AG	acceptor_gain	1.0000
5:306600:A:AT	acceptor_loss	1.0000
5:306600:AGCC:A	acceptor_loss	1.0000
5:306601:G:GG	acceptor_gain	1.0000
5:306601:G:GT	acceptor_loss	1.0000
5:306601:GCC:G	acceptor_gain	1.0000
5:306601:GCCAT:G	acceptor_gain	1.0000
5:306725:A:G	donor_gain	1.0000
5:314549:A:T	donor_gain	1.0000
5:271808:A:T	donor_gain	0.9900
5:271819:GAG:G	donor_gain	0.9900
5:274140:TTC:T	donor_gain	0.9900
5:279092:G:GT	donor_gain	0.9900
5:304222:G:GG	donor_gain	0.9900
5:306601:GC:G	acceptor_gain	0.9900
5:306601:GCCA:G	acceptor_gain	0.9900
5:311288:T:A	acceptor_gain	0.9900
5:311288:T:TA	acceptor_gain	0.9900
5:311288:TGAA:T	acceptor_loss	0.9900
5:311289:GAA:G	acceptor_loss	0.9900
5:311291:A:AG	acceptor_gain	0.9900
5:311291:A:C	acceptor_loss	0.9900
5:311292:G:GA	acceptor_loss	0.9900
5:311292:G:GG	acceptor_gain	0.9900
5:311398:TGCAG:T	donor_loss	0.9900
5:311400:CAGGT:C	donor_loss	0.9900

AlphaMissense

1270 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:271814:T:C	F32L	1.000
5:271816:C:A	F32L	1.000
5:271816:C:G	F32L	1.000
5:272737:T:A	I43K	1.000
5:272752:T:A	L48H	1.000
5:272752:T:C	L48P	1.000
5:272764:T:A	L52H	1.000
5:304191:T:C	F60L	1.000
5:304193:T:A	F60L	1.000
5:304193:T:G	F60L	1.000
5:304207:T:A	V65D	1.000
5:306607:T:C	F72L	1.000
5:306609:T:A	F72L	1.000
5:306609:T:G	F72L	1.000
5:306646:T:C	F85L	1.000
5:306647:T:C	F85S	1.000
5:306648:C:A	F85L	1.000
5:306648:C:G	F85L	1.000
5:306688:T:C	F99L	1.000
5:306689:T:C	F99S	1.000
5:306690:C:A	F99L	1.000
5:306690:C:G	F99L	1.000
5:306700:G:C	D103H	1.000
5:306712:T:C	S107P	1.000
5:306737:T:C	L115P	1.000
5:311370:G:C	D149H	1.000
5:311371:A:T	D149V	1.000
5:311376:T:C	F151L	1.000
5:311377:T:C	F151S	1.000
5:311378:C:A	F151L	1.000

dbSNP variants (sampled 300 via entrez): RS1000043292 (5:308459 G>C), RS1000064262 (5:275557 A>G), RS1000366368 (5:281137 T>G), RS1000426191 (5:303313 CTGTG>C,CTG), RS1000532496 (5:297829 G>A,T), RS1000577549 (5:291942 T>C), RS1000610026 (5:303100 TAGG>T), RS1000775998 (5:310332 A>C), RS1000828805 (5:274778 A>C), RS1000984537 (5:279557 G>A), RS1001029971 (5:291499 C>T), RS1001051900 (5:307440 C>T), RS1001159945 (5:299233 T>A,C,G), RS1001164152 (5:313043 C>T), RS1001250089 (5:279836 G>A,C,T)

Disease associations

OMIM: gene MIM:601057 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST012227_1334	Hip circumference adjusted for BMI	5.000000e-09
GCST90020028_1027	Hip circumference adjusted for BMI	4.000000e-08
GCST90020029_1126	Waist circumference adjusted for body mass index	7.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105994 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.00	Kd	1006	nM	CHEMBL5653589
5.98	ED50	1044	nM	CHEMBL5653589
5.88	Kd	1308	nM	CHEMBL3752910
5.87	ED50	1357	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 7 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148955: Binding affinity to human PDCD6 incubated for 45 mins by Kinobead based pull down assay	kd	1.0059	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148955: Binding affinity to human PDCD6 incubated for 45 mins by Kinobead based pull down assay	kd	1.3084	uM

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, increases expression, decreases reaction, increases abundance	4
Valproic Acid	affects cotreatment, decreases expression	4
sodium arsenite	decreases expression, affects splicing, increases expression	3
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
ginger extract	decreases reaction, increases abundance, increases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
glycidyl methacrylate	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
vanadyl sulfate	increases expression	1
dibenzo(a,l)pyrene	decreases expression	1
microcystin RR	decreases expression	1
CGP 52608	affects binding, increases reaction	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects expression, increases abundance	1
Diethylstilbestrol	increases expression	1
Succimer	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Menthol	decreases expression	1
Methapyrilene	increases methylation	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4012571	Binding	Binding affinity to PDCD6 protein in human INA-6 cells after 3 hrs by nanoLC-MS/MS method	Ugi Reaction-Derived α-Acyl Aminocarboxamides Bind to Phosphatidylinositol 3-Kinase-Related Kinases, Inhibit HSF1-Dependent Heat Shock Response, and Induce Apoptosis in Multiple Myeloma Cells. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3DN	Abcam HEK293T PDCD6 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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