PDCD4

Summary

PDCD4 (programmed cell death 4, HGNC:8763) is a protein-coding gene on chromosome 10q25.2, encoding Programmed cell death protein 4 (Q53EL6). Inhibits translation initiation and cap-dependent translation. In precision oncology, PDCD4 EXPRESSION confers sensitivity to Paclitaxel in Lung Cancer (CIViC Level B).

This gene is a tumor suppressor and encodes a protein that binds to the eukaryotic translation initiation factor 4A1 and inhibits its function by preventing RNA binding. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 27250 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 74 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_014456

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8763
Approved symbol	PDCD4
Name	programmed cell death 4
Location	10q25.2
Locus type	gene with protein product
Status	Approved
Aliases	H731
Ensembl gene	ENSG00000150593
Ensembl biotype	protein_coding
OMIM	608610
Entrez	27250

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 23 protein_coding, 8 protein_coding_CDS_not_defined

ENST00000280154, ENST00000393104, ENST00000444997, ENST00000462577, ENST00000467574, ENST00000481353, ENST00000483595, ENST00000483670, ENST00000489049, ENST00000492932, ENST00000498367, ENST00000888006, ENST00000888007, ENST00000888008, ENST00000888009, ENST00000888010, ENST00000888011, ENST00000888012, ENST00000888013, ENST00000888014, ENST00000888015, ENST00000888016, ENST00000919434, ENST00000919435, ENST00000963371, ENST00000963372, ENST00000963373, ENST00000963374, ENST00000963375, ENST00000963376, ENST00000963377

RefSeq mRNA: 3 — MANE Select: NM_014456 NM_001199492, NM_014456, NM_145341

CCDS: CCDS44478, CCDS7567

Canonical transcript exons

ENST00000280154 — 12 exons

Exon	Start	End
ENSE00001840051	110898028	110900006
ENSE00001922986	110871928	110872018
ENSE00003465513	110890556	110890670
ENSE00003467056	110887665	110887886
ENSE00003498310	110894412	110894522
ENSE00003541455	110895948	110896087
ENSE00003544242	110894091	110894198
ENSE00003548022	110889533	110889630
ENSE00003566915	110875966	110876070
ENSE00003591656	110885253	110885366
ENSE00003591665	110883003	110883097
ENSE00003615472	110881233	110881535

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 99.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 94.8829 / max 2013.3210, expressed in 1812 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107008	78.8805	1811
107017	8.1449	1606
107007	2.8709	1201
107009	2.3967	1078
107006	0.8215	362
107018	0.5878	314
107011	0.4881	178
107010	0.3505	165
107012	0.1484	52
205987	0.0942	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.70	gold quality
skin of abdomen	UBERON:0001416	99.43	gold quality
skin of leg	UBERON:0001511	99.31	gold quality
rectum	UBERON:0001052	99.30	gold quality
right lobe of thyroid gland	UBERON:0001119	99.16	gold quality
left lobe of thyroid gland	UBERON:0001120	99.11	gold quality
minor salivary gland	UBERON:0001830	99.05	gold quality
left ovary	UBERON:0002119	98.99	gold quality
ventricular zone	UBERON:0003053	98.97	gold quality
right ovary	UBERON:0002118	98.96	gold quality
thyroid gland	UBERON:0002046	98.94	gold quality
transverse colon	UBERON:0001157	98.88	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.88	gold quality
mucosa of transverse colon	UBERON:0004991	98.87	gold quality
colonic epithelium	UBERON:0000397	98.86	gold quality
right uterine tube	UBERON:0001302	98.85	gold quality
esophagus mucosa	UBERON:0002469	98.82	gold quality
saliva-secreting gland	UBERON:0001044	98.80	gold quality
adrenal tissue	UBERON:0018303	98.77	gold quality
zone of skin	UBERON:0000014	98.74	gold quality
pancreas	UBERON:0001264	98.66	gold quality
lower esophagus mucosa	UBERON:0035834	98.64	gold quality
mouth mucosa	UBERON:0003729	98.57	gold quality
body of uterus	UBERON:0009853	98.56	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.51	gold quality
adenohypophysis	UBERON:0002196	98.49	gold quality
calcaneal tendon	UBERON:0003701	98.36	gold quality
body of stomach	UBERON:0001161	98.29	gold quality
tonsil	UBERON:0002372	98.26	gold quality
islet of Langerhans	UBERON:0000006	98.11	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-9841	yes	1564.77
E-MTAB-10855	yes	1242.21
E-MTAB-3929	yes	762.86
E-HCAD-6	yes	56.35
E-MTAB-6701	yes	37.58
E-MTAB-6678	yes	24.17
E-CURD-122	yes	23.48
E-MTAB-9388	yes	12.42
E-MTAB-10137	yes	4.60
E-CURD-97	no	2669.12
E-MTAB-7606	no	428.08
E-MTAB-7303	no	230.41
E-CURD-112	no	3.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, MYB, MYC, NFKB1, NFKB, NKX6-3, RELA, SP1, SP3, TP53

miRNA regulators (miRDB)

120 targeting PDCD4, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-613	99.91	71.50	1710

Literature-anchored findings (GeneRIF, showing 40)

• up-regulated in senescent diploid fibroblasts (PMID:12054647)
• Results indicate that not only binding to eIF4A but also prevention of eIF4A binding to the MA-3 domain of eIF4Gc contributes to the mechanism by which Pdcd4 inhibits translation. (PMID:15082783)
• overexpression of PDCD4 in carcinoid cells results in inhibition of cell proliferation. (PMID:15153438)
• expression of pdcd4 as an indirect suppressor of CDK1/cdc2 is lost in progressed carcinomas of lung, breast, colon, and prostate (PMID:15317660)
• Pdcd4 suppresses tumor progression in colon carcinoma cells by the novel mechanism of down-regulating MAP4K1 transcription, with consequent inhibition of c-Jun activation and AP-1-dependent transcription. (PMID:16449643)
• data suggest that PDCD4 is a proapoptotic molecule involved in TGF-beta1-induced apoptosis in human HCC cells, and a possible tumor suppressor in hepatocarcinogenesis (PMID:16682950)
• in response to mitogens, PDCD4 was rapidly phosphorylated by protein kinase S6K1 & then degraded by ubiquitin ligase SCF(betaTRCP); it is proposed that regulated degradation of PDCD4 in response to mitogens allows efficient protein synthesis & cell growth (PMID:17053147)
• These data suggest Pdcd4 as a new negative regulator of intravasation, and qas the invasion-related gene u-PAR. It is the first study to implicate Pdcd4 regulation of gene expression via Sp1/Sp3. (PMID:17297470)
• Downregulation of tumor suppressor Pdcd4 promotes colonic neoplastic transformation and tumor invasion (PMID:17828298)
• Loss of programmed cell death 4 expression is associated with colorectal cancer (PMID:17849461)
• we conclude that the function of Pdcd4 might be cell type specific. A role for Pdcd4 in apoptosis or as a tumor suppressor might be limited to certain cell types. (PMID:17955371)
• Altered cellular localization of PDCD4 when comparing normal breast to neoplastic breast tissue. (PMID:17982621)
• Programmed Cell Death 4 (PDCD4) is regulated by microrna miR-21 and demonstrate that PDCD4 is a functionally important target for miR-21 in breast cancer cells. (PMID:17991735)
• the PDCD4 MA3 domains compete with the eIF4G MA3 domain and RNA for eIF4A binding. PDCD4 inhibits translation initiation by displacing eIF4G and RNA from eIF4A. (PMID:18296639)
• Pdcd4 is a translation inhibitor targeted for degradation during tumor promotion (PMID:18296647)
• mir-21 functions as an oncogene by a mechanism that involves translational repression of the tumor suppressor Pdcd4 (PMID:18372920)
• Suppression of PDCD4 expression is associated with breast cancer cell invasion. (PMID:18386173)
• results provide the first evidence that Pdcd4 is important role in the DNA-damage response and suggest that low levels of Pdcd4 expression observed in certain tumor cells contribute to tumorigenesis by affecting the fate of DNA-damaged cells (PMID:18427550)
• in squamous cell carcinoma lung cancer lines, alterations in Pdcd4 mRNA and protein levels are not directly linked. (PMID:18457901)
• the pathogenesis, development and prognosis of laryngeal carcinoma maybe closely related to the high expression of PD4 and CD44v6, CD44v9 proteins. (PMID:18476625)
• Suppression of Pdcd4 resulted in an increased release of CgA and Sg II and was accompanied by an up-regulation of intracellular PC1. (PMID:18549351)
• PDCD4 5’CpG island methylation blocks PDCD4 expression at mRNA levels in gliomas. (PMID:18793349)
• Inhibition of miR-21 increases endogenous levels of PDCD4 in cell line T98G and over-expression miR-21 inhibits PDCD4-dependent apoptosis (PMID:19013014)
• Lost or reduced PDCD4 expression is associated with the progression of ovarian serous cystadenocarcinomas and may serve as an important prognostic marker. (PMID:19031945)
• Structural and mutational analyses reveal that Pdcd4 inhibits translation initiation by trapping eIF4A in an inactive conformation, and blocking its incorporation into the eIF4F complex. (PMID:19153607)
• reveals insights into the inhibition mechanism of eIF4A by PDCD4 and provides a framework for designing chemicals that target eIF4A (PMID:19204291)
• Inhibitors of miR-21 increased levels of PDCD4 in cholangiocarcinoma. (PMID:19296468)
• PDCD4 inhibits the malignant phenotype of ovarian cancer cells. (PMID:19493270)
• Results indicate that HA binding to CD44 promotes PKCepsilon activation, increases the phosphorylation of the stem cell marker, Nanog, leads to microRNA-21 (miR-21) production and PDCD4 reduction. (PMID:19633292)
• Reducing expression of miR-21 or miR-155 led to up-regulation of phosphatase and tensin homologue (PTEN), programmed cell death 4 (PDCD4), or Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1). (PMID:19641183)
• Identified up-regulation of microRNA-21 (hsa-miR-21) concurrent with down-regulation of potent tumor suppressor proteins PTEN and programmed cell death 4 in cholesteatoma as compared with normal skin. (PMID:19672202)
• miR-21 in HeLa cervical cancer cells caused profound suppression of cell proliferation, and up-regulated the expression of the tumor suppressor gene PDCD4. (PMID:19682430)
• Study demonstrated that the loss of Pdcd4 was a common abnormality at molecular level in ovarian cancer and it might be a potential prognostic factor in ovarian cancer patients. (PMID:19728867)
• Data show that elevated Snail expression by Pdcd4 knockdown leads to downregulation of E-cadherin resulting in activating beta-catenin/Tcf-dependent transcription. (PMID:19784072)
• Recent findings indicate that the microRNA miR-21 posttranscriptionally regulates Pdcd4, as well as invasion, intravasation, and metastasis of colon cancer. (PMID:19836969)
• miR-21 regulates PDCD4 expression after LPS stimulation. (PMID:19946272)
• found that PDCD4 inhibits c-Jun amino-terminal kinase activity resulting in inhibition of the phosphorylation of c-Jun, one isoform of AP-1 (PMID:20359850)
• PDCD4 and microRNA-21 have a role in human gastric cancer (PMID:20372781)
• Two isoforms of PKCs are involved in the regulation of the PDCD4 protein expression related to the proteasomal degradation pathway. (PMID:20471435)
• The loss of Pdcd4 early in cancer progression may have an important role in the increased sensitivity of cancer cells to hypoxia through increased LOX activity and concomitant enhanced invasiveness. (PMID:20498644)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdcd4b	ENSDARG00000041022
mus_musculus	Pdcd4	ENSMUSG00000024975
rattus_norvegicus	Pdcd4	ENSRNOG00000014779
drosophila_melanogaster	Pdcd4	FBGN0030520

Protein

Protein identifiers

Programmed cell death protein 4 — Q53EL6 (reviewed: Q53EL6)

Alternative names: Neoplastic transformation inhibitor protein, Nuclear antigen H731-like, Protein 197/15a

All UniProt accessions (2): Q53EL6, Q5VZS7

UniProt curated annotations — full annotation on UniProt →

Function. Inhibits translation initiation and cap-dependent translation. May excert its function by hindering the interaction between EIF4A1 and EIF4G. Inhibits the helicase activity of EIF4A. Modulates the activation of JUN kinase. Down-regulates the expression of MAP4K1, thus inhibiting events important in driving invasion, namely, MAPK85 activation and consequent JUN-dependent transcription. May play a role in apoptosis. Tumor suppressor. Inhibits tumor promoter-induced neoplastic transformation. Binds RNA.

Subunit / interactions. Interacts (via MI domains) with EIF4A2. Interacts (via MI domains) with EIF4A1 (via N-terminal domain). Heterotrimer with EIF4A1; one molecule of PDCD4 binds two molecules of EIF4A1. Interacts with EIF4G1. May form a complex with EIF4A1 and EIF4G1. The interaction between PDCD4 and EIF4A1 interferes with the interaction between EIF4A1 and EIF4G. When phosphorylated, interacts with BTRC and FBXW11.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Up-regulated in proliferative cells. Highly expressed in epithelial cells of the mammary gland. Reduced expression in lung cancer and colon carcinoma.

Post-translational modifications. Polyubiquitinated, leading to its proteasomal degradation. Rapidly degraded in response to mitogens. Phosphorylation of the phosphodegron promotes interaction with BTRC and proteasomal degradation. Phosphorylated at Ser-67 by RPS6KB1 in response to mitogens; phosphorylation promotes proteasomal degradation of PDCD4.

Domain organisation. Binds EIF4A1 via both MI domains.

Induction. IL2/interleukin-2 stimulation inhibits expression, while IL12/interleukin-12 increases expression.

Similarity. Belongs to the PDCD4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q53EL6-1	1	yes
Q53EL6-2	2

RefSeq proteins (3): NP_001186421, NP_055271, NP_663314 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003891	Initiation_fac_eIF4g_MI	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR039778	PDCD4	Family

Pfam: PF02847

UniProt features (74 total): mutagenesis site 19, helix 17, modified residue 13, sequence conflict 8, sequence variant 3, short sequence motif 3, domain 2, region of interest 2, turn 2, compositionally biased region 2, chain 1, splice variant 1, strand 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
9TES	X-RAY DIFFRACTION	1.22
2RG8	X-RAY DIFFRACTION	1.8
9BKD	ELECTRON MICROSCOPY	2.6
2ZU6	X-RAY DIFFRACTION	2.8
3EIJ	X-RAY DIFFRACTION	2.8
8XXL	ELECTRON MICROSCOPY	2.9
8XXM	ELECTRON MICROSCOPY	3.2
8XXN	ELECTRON MICROSCOPY	3.6
9BLN	ELECTRON MICROSCOPY	3.9
2GGF	SOLUTION NMR
2KZT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53EL6-F1	77.03	0.55

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 (13): 1, 25, 67, 68, 71, 76, 78, 80, 94, 152, 313, 317, 457

Mutagenesis-validated functional residues (19):

Position	Phenotype
67	loss of phosphorylation site. reduces interaction with btrc. abolishes phosphorylation by pkb; when associated with a-45
71	strongly reduced interaction with btrc. strongly reduced ubiquitination.
76	strongly reduced interaction with btrc. strongly reduced ubiquitination.
174	reduced inhibition of eif4a1 helicase activity.
210	reduced inhibition of eif4a1 helicase activity. strongly reduced inhibition of translation.
249	reduced interaction with eif4a1.
252	strongly reduced interaction with eif4a1. reduced inhibition of eif4a1 helicase activity. strongly reduced inhibition of
253	strongly reduced interaction with eif4a1. strongly reduced inhibition of translation. reduced inhibition of eif4a1 helic
255	reduced inhibition of eif4a1 helicase activity. strongly reduced inhibition of translation.
333	no effect on inhibition of eif4a1 and on inhibition of translation; when associated with a-340.
337	no effect on inhibition of eif4a1 and on inhibition of translation.
340	no effect on inhibition of eif4a1 and on inhibition of translation; when associated with a-333.
358	strongly reduced interaction with eif4a1.
359	strongly reduced inhibition of eif4a1. strongly reduced inhibition of translation.
361	strongly reduced inhibition of eif4a1. strongly reduced inhibition of translation.
414	strongly reduced interaction with eif4a1. strongly reduced inhibition of translation.
418	reduced interaction with eif4a1. strongly reduced inhibition of translation.
420	strongly reduced interaction with eif4a1. strongly reduced inhibition of translation.
457	loss of phosphorylation site, and loss of nuclear accumulation. abolishes phosphorylation by pkb; when associated with a

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8950505	Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation

MSigDB gene sets: 457 (showing top): GOBP_NEGATIVE_REGULATION_OF_MAP_KINASE_ACTIVITY, KOBAYASHI_EGFR_SIGNALING_24HR_UP, JI_RESPONSE_TO_FSH_UP, HNF3ALPHA_Q6, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_SMOOTH_MUSCLE_CELL_DIFFERENTIATION, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS

GO Biological Process (14): apoptotic process (GO:0006915), BMP signaling pathway (GO:0030509), negative regulation of JUN kinase activity (GO:0043508), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of inflammatory response (GO:0050729), epithelial to mesenchymal transition involved in cardiac fibroblast development (GO:0060940), cellular response to lipopolysaccharide (GO:0071222), negative regulation of cytokine production involved in inflammatory response (GO:1900016), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), negative regulation of vascular associated smooth muscle cell proliferation (GO:1904706), negative regulation of myofibroblast differentiation (GO:1904761), negative regulation of vascular associated smooth muscle cell differentiation (GO:1905064), positive regulation of vascular associated smooth muscle cell apoptotic process (GO:1905461), positive regulation of endothelial cell apoptotic process (GO:2000353)

GO Molecular Function (2): RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Interleukin-12 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
JUN kinase activity	1
negative regulation of MAP kinase activity	1
regulation of JUN kinase activity	1
negative regulation of JNK cascade	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
cardiac epithelial to mesenchymal transition	1
epicardium-derived cardiac fibroblast cell development	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
negative regulation of cytokine production	1
cytokine production involved in inflammatory response	1
regulation of cytokine production involved in inflammatory response	1
non-canonical NF-kappaB signal transduction	1
regulation of non-canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
negative regulation of smooth muscle cell proliferation	1
regulation of vascular associated smooth muscle cell proliferation	1
vascular associated smooth muscle cell proliferation	1
myofibroblast differentiation	1
negative regulation of cell differentiation	1
regulation of myofibroblast differentiation	1
vascular associated smooth muscle cell differentiation	1
negative regulation of smooth muscle cell differentiation	1
regulation of vascular associated smooth muscle cell differentiation	1
positive regulation of smooth muscle cell apoptotic process	1
vascular associated smooth muscle cell apoptotic process	1

Protein interactions and networks

STRING

2008 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDCD4	EIF4A1	P04765	997
PDCD4	EIF4A2	Q14240	997
PDCD4	EIF4G1	Q04637	965
PDCD4	DROSHA	Q9NRR4	918
PDCD4	RPS6KB1	P23443	820
PDCD4	EIF4E	P06730	801
PDCD4	PTEN	P60484	799
PDCD4	RECK	O95980	793
PDCD4	EIF4B	P23588	784
PDCD4	SMAD5	Q99717	765
PDCD4	DDX5	P17844	760
PDCD4	BTRC	Q9Y297	757
PDCD4	AGO2	Q9UKV8	749
PDCD4	SMAD4	Q13485	740
PDCD4	RPS13	P19116	724

IntAct

121 interactions, top by confidence:

A	B	Type	Score
EIF4A3	CASC3	psi-mi:“MI:0914”(association)	0.980
EIF4A1	PDCD4	psi-mi:“MI:0407”(direct interaction)	0.950
EIF4A1	PDCD4	psi-mi:“MI:0915”(physical association)	0.950
PDCD4	EIF4A1	psi-mi:“MI:0914”(association)	0.950
EIF4A3	PDCD4	psi-mi:“MI:0915”(physical association)	0.780
PDCD4	EIF4A3	psi-mi:“MI:0915”(physical association)	0.780
EIF4A2	PDCD4	psi-mi:“MI:0915”(physical association)	0.680
PDCD4	EIF4A2	psi-mi:“MI:0915”(physical association)	0.680
TGIF2LY	PGP	psi-mi:“MI:0914”(association)	0.640
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
PDCD4	RELA	psi-mi:“MI:0915”(physical association)	0.600
RELA	PDCD4	psi-mi:“MI:0915”(physical association)	0.600
RELA	PDCD4	psi-mi:“MI:0403”(colocalization)	0.600
EIF4A2	PDCD4	psi-mi:“MI:0915”(physical association)	0.560
PDCD4	RPL5	psi-mi:“MI:0915”(physical association)	0.550
EIF4A1	EIF3D	psi-mi:“MI:0914”(association)	0.530
COMTD1	IFRD1	psi-mi:“MI:0914”(association)	0.530

BioGRID (254): PDCD4 (Affinity Capture-MS), PDCD4 (Two-hybrid), PDCD4 (Two-hybrid), PDCD4 (Biochemical Activity), PDCD4 (Affinity Capture-MS), PDCD4 (Affinity Capture-MS), PDCD4 (Affinity Capture-MS), PDCD4 (Affinity Capture-MS), PDCD4 (Affinity Capture-MS), PDCD4 (Affinity Capture-MS), PDCD4 (Affinity Capture-Western), PDCD4 (Affinity Capture-Western), PDCD4 (Affinity Capture-MS), PDCD4 (Affinity Capture-Western), PDCD4 (Affinity Capture-RNA)

ESM2 similar proteins: B3MS75, B3NU52, B4GW22, B4I0W6, B4JM29, B4L2J8, B4M7T6, B4NC41, B4Q034, F4IDJ0, F4IUX6, O00203, O35638, Q10LJ0, Q13367, Q16UN6, Q29G82, Q32PG1, Q3UFM5, Q4S6U8, Q52KN9, Q53EL6, Q5MIZ7, Q5R8S3, Q5SP90, Q61823, Q6DFT3, Q6IN85, Q6INN7, Q6NXC0, Q6P2K6, Q7K4N3, Q7PX35, Q7SYB2, Q7YRF1, Q7ZX60, Q801Q7, Q8LNU5, Q8R3N6, Q8RW96

Diamond homologs: B9FXV5, O80548, Q53EL6, Q61823, Q8W4Q4, Q94BR1, Q98TX3, Q9JID1, Q9STL9, Q5R8S3, O43432, P78344, P79398, Q03387, Q5R7J9, Q62448, Q6K641, Q80XI3, Q84PB3, Q93ZT6, Q95L46, Q41583, G5CEW6

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
AKT	down-regulates	PDCD4	phosphorylation
RPS6KB1	down-regulates	PDCD4	phosphorylation
BTRC	down-regulates	PDCD4	ubiquitination
RPS6KB2	down-regulates	PDCD4	phosphorylation
AKT1	down-regulates	PDCD4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 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
Deadenylation of mRNA	5	26.8×	4e-05
Translation initiation complex formation	11	25.5×	5e-11
Ribosomal scanning and start codon recognition	11	25.5×	5e-11
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	7	23.2×	9e-07
Formation of the ternary complex, and subsequently, the 43S complex	8	21.0×	2e-07
Replacement of protamines by nucleosomes in the male pronucleus	6	19.9×	2e-05
M-decay: degradation of maternal mRNAs by maternally stored factors	5	19.9×	8e-05
L13a-mediated translational silencing of Ceruloplasmin expression	14	17.2×	1e-11

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	5	56.7×	5e-06
translational initiation	9	32.6×	6e-09
cytoplasmic translation	9	16.8×	1e-06
rhythmic process	6	15.2×	5e-04
positive regulation of translation	6	13.8×	7e-04
ribosomal small subunit biogenesis	5	11.5×	7e-03
translation	8	8.3×	7e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	0
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2078 predictions. Top by Δscore:

Variant	Effect	Δscore
10:110872052:G:GT	donor_gain	1.0000
10:110881228:TTAA:T	acceptor_loss	1.0000
10:110881229:TAA:T	acceptor_loss	1.0000
10:110881230:A:AG	acceptor_gain	1.0000
10:110881230:AAG:A	acceptor_loss	1.0000
10:110881231:A:AC	acceptor_loss	1.0000
10:110881231:A:AG	acceptor_gain	1.0000
10:110881232:G:GG	acceptor_gain	1.0000
10:110881264:C:CA	acceptor_gain	1.0000
10:110881265:G:A	acceptor_gain	1.0000
10:110881372:GCGAC:G	donor_gain	1.0000
10:110882985:A:AG	acceptor_gain	1.0000
10:110882985:AAT:A	acceptor_gain	1.0000
10:110882986:A:G	acceptor_gain	1.0000
10:110882987:T:G	acceptor_gain	1.0000
10:110882991:A:AG	acceptor_gain	1.0000
10:110882992:A:G	acceptor_gain	1.0000
10:110882993:A:AG	acceptor_gain	1.0000
10:110882998:TTCAG:T	acceptor_loss	1.0000
10:110883000:CAG:C	acceptor_loss	1.0000
10:110883001:AGGT:A	acceptor_gain	1.0000
10:110883002:GGT:G	acceptor_gain	1.0000
10:110883002:GGTG:G	acceptor_gain	1.0000
10:110883096:AGGTA:A	donor_loss	1.0000
10:110883097:GGTAT:G	donor_loss	1.0000
10:110883098:G:GA	donor_loss	1.0000
10:110883099:T:A	donor_loss	1.0000
10:110885249:A:AG	acceptor_gain	1.0000
10:110885249:AAAG:A	acceptor_gain	1.0000
10:110885250:A:G	acceptor_gain	1.0000

AlphaMissense

3074 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:110881531:G:C	K114N	1.000
10:110881531:G:T	K114N	1.000
10:110883026:T:A	W124R	1.000
10:110883026:T:C	W124R	1.000
10:110883028:G:C	W124C	1.000
10:110883028:G:T	W124C	1.000
10:110881521:G:A	G111E	0.999
10:110881529:A:G	K114E	0.999
10:110881532:A:G	K115E	0.999
10:110881534:A:C	K115N	0.999
10:110881534:A:T	K115N	0.999
10:110883012:G:A	G119E	0.999
10:110883029:G:C	G125R	0.999
10:110889540:G:A	G262D	0.999
10:110889557:G:C	A268P	0.999
10:110890572:G:C	A298P	0.999
10:110890623:T:A	W315R	0.999
10:110890623:T:C	W315R	0.999
10:110894175:T:C	F359L	0.999
10:110894177:T:A	F359L	0.999
10:110894177:T:G	F359L	0.999
10:110894412:G:C	A367P	0.999
10:110895948:G:C	G404R	0.999
10:110895949:G:A	G404D	0.999
10:110895959:A:C	R407S	0.999
10:110895959:A:T	R407S	0.999
10:110898033:G:C	R452T	0.999
10:110898034:A:C	R452S	0.999
10:110898034:A:T	R452S	0.999
10:110898038:C:A	R454S	0.999

dbSNP variants (sampled 300 via entrez): RS1000017355 (10:110871845 C>A,G,T), RS1000056963 (10:110873634 C>T), RS1000072080 (10:110871624 C>G), RS1000097071 (10:110890087 A>G), RS1000128935 (10:110886853 A>C,G), RS1000189258 (10:110871529 G>C), RS1000311563 (10:110876937 G>A), RS1000427214 (10:110889389 GT>G,GTT,GTTT), RS1000654350 (10:110872544 C>G,T), RS1000706130 (10:110878697 G>C), RS1000729151 (10:110871715 C>A,G,T), RS1000735751 (10:110885169 C>T), RS1000794209 (10:110883900 A>G), RS1000901967 (10:110877563 A>G), RS1000919483 (10:110872349 C>G,T)

Disease associations

OMIM: gene MIM:608610 | disease phenotypes: MIM:613172

GenCC curated gene-disease

Mondo (1): dilated cardiomyopathy 1DD (MONDO:0013168)

Orphanet (1): Familial isolated dilated cardiomyopathy (Orphanet:154)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010142_18	Fish- and plant-related diet	3.000000e-10
GCST010142_84	Fish- and plant-related diet	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567725	Cardiomyopathy, Dilated, 1DD (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1781868 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 172,798 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL413	SIROLIMUS	4	172,798

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
PDCD4 EXPRESSION	Paclitaxel	Lung Cancer	Sensitivity/Response	CIViC B	EID821

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

ChEMBL bioactivities

13 potent at pChembl≥5 of 13 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.30	EC50	50	nM	SIROLIMUS
6.90	Kd	126.9	nM	CHEMBL5653589
6.90	ED50	126.9	nM	CHEMBL5653589
6.06	IC50	880	nM	TUBERCIDIN
5.89	EC50	1300	nM	CRYPTOCARYOL G
5.82	EC50	1500	nM	CRYPTOCARYOL D
5.80	EC50	1600	nM	CRYPTOCARYOL C
5.75	EC50	1800	nM	CRYPTOCARYOL E
5.75	EC50	1800	nM	CRYPTOCARYOL H
5.65	EC50	2251	nM	CHEMBL5170759
5.52	EC50	3000	nM	CRYPTOCARYOL B
5.46	EC50	3500	nM	CRYPTOCARYOL F
5.31	EC50	4900	nM	CRYPTOCARYOL A

PubChem BioAssay actives

12 with measured affinity, of 62 total; 12 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
Sirolimus	601333: Inhibition of TPA-induced degradation of Pdcd4 (amino acid 39-91) expressed in human HEK293 cells assessed as minimum compound concentration required for 50% recovery of Pdcd4-luciferase signal incubated for 8 hrs by luciferase reporter gene assay	ec50	0.0500	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148953: Binding affinity to human PDCD4 incubated for 45 mins by Kinobead based pull down assay	kd	0.1269	uM
(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)oxolane-3,4-diol	626968: Stabilization of Pdcd4 expressed in human HEK293 cells assessed as inhibition of TPA-induced degradation by luciferase reporter assay	ic50	0.8800	uM
(2S,3S)-3-hydroxy-2-[(Z,2S,4S,6S,8R)-2,4,6,8-tetrahydroxytetratriacont-21-enyl]-2,3-dihydropyran-6-one	601333: Inhibition of TPA-induced degradation of Pdcd4 (amino acid 39-91) expressed in human HEK293 cells assessed as minimum compound concentration required for 50% recovery of Pdcd4-luciferase signal incubated for 8 hrs by luciferase reporter gene assay	ec50	1.3000	uM
[(2S,4S,6R,8R,10R)-2,4,6,8-tetrahydroxy-1-[(2S,3S)-3-hydroxy-6-oxo-2,3-dihydropyran-2-yl]pentacosan-10-yl] acetate	601333: Inhibition of TPA-induced degradation of Pdcd4 (amino acid 39-91) expressed in human HEK293 cells assessed as minimum compound concentration required for 50% recovery of Pdcd4-luciferase signal incubated for 8 hrs by luciferase reporter gene assay	ec50	1.5000	uM
(2S,3S)-3-hydroxy-2-[(2S,4S,6S,8S,10R)-2,4,6,8,10-pentahydroxypentacosyl]-2,3-dihydropyran-6-one	601333: Inhibition of TPA-induced degradation of Pdcd4 (amino acid 39-91) expressed in human HEK293 cells assessed as minimum compound concentration required for 50% recovery of Pdcd4-luciferase signal incubated for 8 hrs by luciferase reporter gene assay	ec50	1.6000	uM
(2S,3S)-3-hydroxy-2-[(Z,2S,4S,6R)-2,4,6-trihydroxydotriacont-19-enyl]-2,3-dihydropyran-6-one	601333: Inhibition of TPA-induced degradation of Pdcd4 (amino acid 39-91) expressed in human HEK293 cells assessed as minimum compound concentration required for 50% recovery of Pdcd4-luciferase signal incubated for 8 hrs by luciferase reporter gene assay	ec50	1.8000	uM
(2S,3S)-3-hydroxy-2-[(2S,4S,6S,8R)-2,4,6,8-tetrahydroxytricosyl]-2,3-dihydropyran-6-one	601333: Inhibition of TPA-induced degradation of Pdcd4 (amino acid 39-91) expressed in human HEK293 cells assessed as minimum compound concentration required for 50% recovery of Pdcd4-luciferase signal incubated for 8 hrs by luciferase reporter gene assay	ec50	1.8000	uM
ethyl 2-(4-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylate	1884647: Inhibition of PDCD4 in human HeLa cells tranfected with pCI-neo-luciferase-PDCD4 3’-UTR plasmid assessed as increase in luciferase activity by luciferase reporter assay	ec50	2.2510	uM
[(2S,4S,6R,8R,10R)-2,4,6,8-tetrahydroxy-1-[(2R)-6-oxo-2,3-dihydropyran-2-yl]pentacosan-10-yl] acetate	601333: Inhibition of TPA-induced degradation of Pdcd4 (amino acid 39-91) expressed in human HEK293 cells assessed as minimum compound concentration required for 50% recovery of Pdcd4-luciferase signal incubated for 8 hrs by luciferase reporter gene assay	ec50	3.0000	uM
(2S,3S)-3-hydroxy-2-[(Z,2S,4S,6S,8S,10R)-2,4,6,8,10-pentahydroxyhexatriacont-23-enyl]-2,3-dihydropyran-6-one	601333: Inhibition of TPA-induced degradation of Pdcd4 (amino acid 39-91) expressed in human HEK293 cells assessed as minimum compound concentration required for 50% recovery of Pdcd4-luciferase signal incubated for 8 hrs by luciferase reporter gene assay	ec50	3.5000	uM
(2R)-2-[(2S,4S,6S,8S,10R)-2,4,6,8,10-pentahydroxypentacosyl]-2,3-dihydropyran-6-one	601333: Inhibition of TPA-induced degradation of Pdcd4 (amino acid 39-91) expressed in human HEK293 cells assessed as minimum compound concentration required for 50% recovery of Pdcd4-luciferase signal incubated for 8 hrs by luciferase reporter gene assay	ec50	4.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, decreases methylation, affects cotreatment	9
Resveratrol	affects cotreatment, increases expression, increases stability, affects response to substance	5
Arsenic Trioxide	increases expression	5
Estradiol	increases expression, decreases reaction, decreases expression, increases reaction, affects reaction	5
chromium hexavalent ion	decreases expression, decreases reaction, affects reaction	3
Benzo(a)pyrene	decreases expression, increases expression	3
Quercetin	affects cotreatment, decreases reaction, increases expression, decreases expression	3
Cadmium Chloride	decreases expression, increases expression	3
Sirolimus	increases reaction, affects cotreatment, increases stability, increases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases methylation, increases expression	2
arsenite	decreases expression, affects binding, decreases reaction	2
cobaltous chloride	decreases expression, increases expression	2
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases reaction, increases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Dimethyl Sulfoxide	increases expression	2
Dust	decreases expression, increases expression	2
Hydrogen Peroxide	affects expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tretinoin	decreases expression, increases response to substance, affects localization, increases expression, increases reaction	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	decreases expression	2
Genistein	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
afuresertib	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
urushiol	increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1787264	Binding	Inhibition of TPA-induced degradation of Pdcd4 (amino acid 39-91) expressed in human HEK293 cells assessed as minimum compound concentration required for 50% recovery of Pdcd4-luciferase signal incubated for 8 hrs by luciferase reporter gen	Cryptocaryols A-H, α-pyrone-containing 1,3-polyols from Cryptocarya sp. implicated in stabilizing the tumor suppressor Pdcd4. — J Nat Prod

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2A6	Abcam HeLa PDCD4 KO	Cancer cell line	Female
CVCL_TC60	HAP1 PDCD4 (-) 1	Cancer cell line	Male
CVCL_TC61	HAP1 PDCD4 (-) 2	Cancer cell line	Male
CVCL_ZJ06	LanthaScreen PDCD4 HEK 293E	Transformed cell line	Female

Clinical trials (associated diseases)

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