PODXL

Summary

PODXL (podocalyxin like, HGNC:9171) is a protein-coding gene on chromosome 7q32.3, encoding Podocalyxin (O00592). Involved in the regulation of both adhesion and cell morphology and cancer progression. It is a selective cancer dependency (DepMap: 19.4% of cell lines).

This gene encodes a member of the sialomucin protein family. The encoded protein was originally identified as an important component of glomerular podocytes. Podocytes are highly differentiated epithelial cells with interdigitating foot processes covering the outer aspect of the glomerular basement membrane. Other biological activities of the encoded protein include: binding in a membrane protein complex with Na+/H+ exchanger regulatory factor to intracellular cytoskeletal elements, playing a role in hematopoetic cell differentiation, and being expressed in vascular endothelium cells and binding to L-selectin.

Source: NCBI Gene 5420 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephrotic syndrome (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 269 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 74
• Cancer dependency (DepMap): dependent in 19.4% of screened cell lines
• MANE Select transcript: NM_001018111

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9171
Approved symbol	PODXL
Name	podocalyxin like
Location	7q32.3
Locus type	gene with protein product
Status	Approved
Aliases	PCLP, Gp200, PC, PODXL1, PDX, gp135
Ensembl gene	ENSG00000128567
Ensembl biotype	protein_coding
OMIM	602632
Entrez	5420

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 18 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000322985, ENST00000378555, ENST00000446198, ENST00000465001, ENST00000482581, ENST00000484346, ENST00000487965, ENST00000490761, ENST00000875715, ENST00000875716, ENST00000875717, ENST00000875718, ENST00000875719, ENST00000875720, ENST00000875721, ENST00000923667, ENST00000923668, ENST00000923669, ENST00000923670, ENST00000923671, ENST00000923672, ENST00000923673, ENST00000923674, ENST00000923675

RefSeq mRNA: 2 — MANE Select: NM_001018111 NM_001018111, NM_005397

CCDS: CCDS34755, CCDS47714

Canonical transcript exons

ENST00000378555 — 9 exons

Exon	Start	End
ENSE00000882387	131509365	131509585
ENSE00001387062	131510828	131511433
ENSE00001477922	131508951	131509028
ENSE00001847109	131556260	131556628
ENSE00002439128	131510236	131510331
ENSE00003514466	131505868	131506035
ENSE00003608217	131506260	131506321
ENSE00003664504	131506579	131506726
ENSE00003850906	131500271	131504508

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 99.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 77.2732 / max 2491.7323, expressed in 1476 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86278	56.1602	1355
86277	7.7138	1180
86272	4.1840	746
86276	2.3756	757
204775	1.8723	669
86271	1.7999	521
86269	0.9997	356
86274	0.5852	260
86273	0.4668	236
86266	0.3913	152

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal glomerulus	UBERON:0000074	99.69	gold quality
metanephric glomerulus	UBERON:0004736	99.64	gold quality
germinal epithelium of ovary	UBERON:0001304	99.19	gold quality
parietal pleura	UBERON:0002400	98.17	gold quality
right lung	UBERON:0002167	97.68	gold quality
metanephros	UBERON:0000081	97.58	gold quality
adult mammalian kidney	UBERON:0000082	97.58	gold quality
pleura	UBERON:0000977	97.44	gold quality
visceral pleura	UBERON:0002401	97.21	gold quality
renal medulla	UBERON:0000362	96.86	gold quality
lower lobe of lung	UBERON:0008949	96.45	gold quality
seminal vesicle	UBERON:0000998	96.44	gold quality
kidney	UBERON:0002113	96.33	gold quality
tendon of biceps brachii	UBERON:0008188	96.29	gold quality
metanephros cortex	UBERON:0010533	96.25	gold quality
left ventricle myocardium	UBERON:0006566	95.92	gold quality
kidney epithelium	UBERON:0004819	95.91	gold quality
apex of heart	UBERON:0002098	95.88	gold quality
upper lobe of lung	UBERON:0008948	95.61	gold quality
upper lobe of left lung	UBERON:0008952	95.50	gold quality
cortex of kidney	UBERON:0001225	95.39	gold quality
adult organism	UBERON:0007023	95.28	gold quality
sural nerve	UBERON:0015488	95.14	gold quality
lung	UBERON:0002048	94.87	gold quality
body of pancreas	UBERON:0001150	94.69	gold quality
myocardium	UBERON:0002349	94.66	gold quality
medial globus pallidus	UBERON:0002477	94.61	gold quality
urethra	UBERON:0000057	94.43	gold quality
decidua	UBERON:0002450	94.29	gold quality
left uterine tube	UBERON:0001303	94.11	gold quality

Single-cell (SCXA)

Detected in 23 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-GEOD-114530	yes	4235.96
E-HCAD-10	yes	2180.39
E-GEOD-124472	yes	1863.89
E-GEOD-109979	yes	1214.51
E-GEOD-135922	yes	1007.72
E-ENAD-27	yes	885.89
E-MTAB-10137	yes	717.57
E-GEOD-36552	yes	571.16
E-GEOD-81608	yes	492.64
E-MTAB-10018	yes	416.07
E-MTAB-10287	yes	44.25
E-MTAB-8410	yes	32.27
E-CURD-119	yes	31.65
E-HCAD-35	yes	23.84
E-MTAB-9388	yes	10.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, TP53, VDR, WT1

miRNA regulators (miRDB)

130 targeting PODXL, 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-3925-3P	100.00	69.95	1237
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-34A-5P	99.99	71.21	1784
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-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-8067	99.86	69.59	2260

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 19.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• podocalyxin has a role in defining the structure of the podocyte basal surface (PMID:15226400)
• Overexpression of the anti-adhesin podocalyxin is associated with breast cancer progression (PMID:15289306)
• PODXL variants are implicated in prostate neoplasm aggressiveness, with gene mapping to chromosome 7q32-q33. (PMID:16434482)
• Transcriptional regulation of Podxl is supported primarily by Sp1 site(s) and that DNA-methylation of the CpG promoter islands contributes to control the tissue specific expression of podxl. (PMID:16684343)
• Embryonal carcinoma expresses two distinct forms of podocalyxin, and the larger version is a molecular carrier of the human stem cell-defining antigens TRA-1-60 and TRA-1-81. [TRA-1-60 AND TRA-1-81 AND podocalyxin] (PMID:17124010)
• 44% of pancreatic ductal adenocarcinomas expressed PODXL-1 in a membranous pattern, and there was no expression in intrahepatic cholangiocarcinomas, rarely in adenocarcinomas of the extrahepatic bile ducts, and none in duodenal adenocarcinomas. (PMID:17137615)
• Podocalyxin defines apical membrane domains and is a potent inducer of microvillus formation (PMID:17311105)
• podocalyxin leads to increased in vitro migration and invasion, increased MMP expression, and increased activation of MAPK and PI3K activity in MCF7 and PC3 cells through its ability to form a complex with ezrin (PMID:17616675)
• A 2315-Da peptide found only in medium from SFC colon cancer cell lines was identified and shown to consist of a portion of both the extracellular and transmembrane regions of human podocalyxin-like 1. (PMID:17719804)
• Our results suggest that aggregated distribution of TRA-1-81 antigen is characteristic for undifferentiated hES cells. (PMID:18313397)
• A monoclonal antibody-antigen complex reveals the presence podocalyxin-like protein-1 in undifferentiated embryonic stem cells. (PMID:18356574)
• Results suggest that human podocalyxin enhances the adherence of cells to immobilized ligands and to vascular endothelial cells through a mechanism(s) dependent on the activity of integrins. (PMID:18456258)
• PODXL(hi)/CD49f(hi) MSCs were less prone to produce lethal pulmonary emboli (PMID:18818395)
• Podocalyxin-like protein is an E-/L-selectin ligand on colon carcinoma cells: comparative biochemical properties of selectin ligands in host and tumor cells. (PMID:19118161)
• Impaired WT1/Cre-binding protein interplay in addition to advanced glycation end products suppress podocalyxin expression in high glucose-treated human podocytes. (PMID:19605546)
• Data show that podocalyxin overexpression in human embryonic kidney cells up-regulates Rac1 activity, which depends on a complex formed by podocalyxin, ERM-binding phosphoprotein 50, ezrin, and ARHGEF7, a Rac1 activator. (PMID:20395446)
• In pluripotent stem cells and in human cancer disease, podocalyxin may function in part to regulate and maintain the cell surface expression of the glucose-3-transporter. (PMID:20599725)
• This report identifies DNA methylation, miR-199a dysregulation and PODXL as critical factors in tumor malignancy. (PMID:21383689)
• PINCH1 is transcriptional regulator in podocytes that interacts with WT1 and represses podocalyxin expression. (PMID:21390327)
• intact PODXL is released to the extracellular space as a cargo of microvesicles and also as a soluble cleaved fragment of ectodomain (PMID:21616097)
• The urinary mRNA profiles of synaptopodin, podocalyxin, CD2-AP, alpha-actin4, and podocin were found to increase with the progression of diabetic nephropathy. (PMID:21655212)
• Podocalyxin-like 1 expression is an independent factor of poor prognosis in colorectal carcinoma. (PMID:21829192)
• podocalyxin’s ability to facilitate the formation of non-adhesive membrane domains may contribute to the formation of free-floating high grade serous tumor nodules during the initial steps of transperitoneal metastasis. (PMID:22262060)
• Most AML patients had a significant decrease in miR-199b-5p levels with elevated PODXL & DDR1 expressions. Both PODXL & DDR1 are targets of miR-199b-5p. (PMID:22374871)
• Levels of urinary PCX and the number of urinary podocytes are associated with histologic abnormalities in adults with IgA nephropathy. (PMID:22700887)
• PODXL protein expression was analyzed n tissue microarrays with colorectal cancer tumor samples. High PODXL protein expression was significantly associated with unfavourable clinicopathological characteristics in both cohorts. (PMID:22769594)
• Sialofucosylated PODXL is a functional E-and L-selectin ligand expressed by metastatic pancreatic cancer cells. (PMID:22814396)
• PODXL has the potential to be a useful biomarker for identifying good prognosis patients in characteristically poor prognosis breast cancer groups and may impact treatment of women with this disease. (PMID:23288345)
• The results obtained indicate that integrity of the PODXL ectodomain is essential for enhancing cell adhesion but not migration, while the integrity of the cytoplasmic domain is required for both adhesion and migration. (PMID:23396057)
• podocalyxin, a heavily glycosylated type 1 transmembrane protein, is a glycoprotein ligand of recombinant N-terminal domain of the lectin BC2L-C from Burkholderia cenocepacia on human induced pluripotent stem cells and embryonic stem cells. (PMID:23526252)
• Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer (PMID:23652315)
• Suggest that analysis of PODXL expression in the primary tumour is sufficient for its use as a prognostic and treatment predictive biomarker in colorectal cancer, also in patients with metastatic disease. (PMID:23819542)
• A variant form of PODXL remains the most likely candidate causing focal and segmental glomerulosclerosis in a family with autosomal dominant inheritance. (PMID:24048372)
• Urinary Podocalyxin positive-element may be a noninvasive marker for the early stage of Diabetic nephropathy. (PMID:24075693)
• TRA-1-81 is expressed only in the cytoplasm of uterine smooth muscle neoplasms. (PMID:24143384)
• PODXL is expressed in glioblastoma multiforme stem-like cells and is involved in cell proliferation and oncosphere formation. (PMID:24146797)
• overexpression of PODXL may be associated with human oral squamous cell carcinoma aggressiveness (PMID:24821609)
• These findings show that overexpression of PODXL enhanced invadopodia formation and tumor metastasis by inducing Rac1/Cdc42/cortactin signaling network. (PMID:24970760)
• miR-125b was found to be important in arteriosclerosis obliterans by suppressing the expression of PODXL and may serve as a potential therapeutic target for the treatment of arteriosclerosis obliterans. (PMID:25738314)
• We show that podocalyxin plays a key role in the formation of primary tumors and distant tumor metastasis. (PMID:25887862)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	podxl	ENSDARG00000031228
mus_musculus	Podxl	ENSMUSG00000025608
rattus_norvegicus	Podxl	ENSRNOG00000012495

Protein

Protein identifiers

Podocalyxin — O00592 (reviewed: O00592)

Alternative names: GCTM-2 antigen, Gp200, Podocalyxin-like protein 1

All UniProt accessions (2): O00592, G3V0E6

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the regulation of both adhesion and cell morphology and cancer progression. Functions as an anti-adhesive molecule that maintains an open filtration pathway between neighboring foot processes in the podocyte by charge repulsion. Acts as a pro-adhesive molecule, enhancing the adherence of cells to immobilized ligands, increasing the rate of migration and cell-cell contacts in an integrin-dependent manner. Induces the formation of apical actin-dependent microvilli. Involved in the formation of a preapical plasma membrane subdomain to set up initial epithelial polarization and the apical lumen formation during renal tubulogenesis. Plays a role in cancer development and aggressiveness by inducing cell migration and invasion through its interaction with the actin-binding protein EZR. Affects EZR-dependent signaling events, leading to increased activities of the MAPK and PI3K pathways in cancer cells.

Subunit / interactions. Monomer; when associated with the membrane raft. Oligomer; when integrated in the apical membrane. Interacts (via the C-terminal PDZ-binding motif DTHL) with NHERF1 (via the PDZ domains); the interaction is not detected in glomerular epithelium cells, take place early in the secretory pathway and is necessary for its apical membrane sorting. Found in a complex with EZR, PODXL and NHERF2. Associates with the actin cytoskeleton through complex formation with EZR and NHERF2. Interacts (via the C-terminal PDZ-binding motif DTHL) with NHERF2 (via the PDZ 1 domain); interaction is detected in glomerular epithelium cells. Interacts with EZR.

Subcellular location. Apical cell membrane. Cell projection. Lamellipodium. Filopodium. Ruffle. Microvillus. Membrane raft. Membrane.

Tissue specificity. Glomerular epithelium cell (podocyte).

Post-translational modifications. N- and O-linked glycosylated. Sialoglycoprotein.

Domain organisation. Both the O-glycan-rich domain of the extracellular domain and the C-terminus PDZ-binding motif (DTHL) in the cytoplasmic tail harbor an apical sorting signal. The cytoplasmic domain is necessary for the apical membrane targeting and renal tubulogenesis. The cytoplasmic C-terminus PDZ-binding motif (DTHL) is essential for interaction with NHERF1 and for targeting NHERF1 to the apical cell membrane. The extracellular domain is necessary for microvillus formation. The large highly anionic extracellular domain allows to maintain open filtration pathways between neighboring podocyte foot processes.

Similarity. Belongs to the podocalyxin family.

Isoforms (2)

UniProt ID	Names	Canonical?
O00592-1	1	yes
O00592-2	2

RefSeq proteins (2): NP_001018121, NP_005388 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013836	CD34/Podocalyxin	Family
IPR017403	PODXL	Family

Pfam: PF06365

UniProt features (34 total): compositionally biased region 8, sequence variant 6, glycosylation site 5, modified residue 4, region of interest 3, topological domain 2, sequence conflict 2, signal peptide 1, chain 1, splice variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00592-F1	53.66	0.05

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 (4): 518, 529, 537, 556

Glycosylation sites (5): 33, 43, 104, 144, 360

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 594 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_NADPPLUS_METABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, AREB6_01, MITSIADES_RESPONSE_TO_APLIDIN_DN, GENTILE_RESPONSE_CLUSTER_D3, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOCC_RUFFLE, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN

GO Biological Process (10): cell adhesion (GO:0007155), negative regulation of cell adhesion (GO:0007162), cell migration (GO:0016477), negative regulation of cell-cell adhesion (GO:0022408), positive regulation of cell migration (GO:0030335), regulation of microvillus assembly (GO:0032534), positive regulation of cell-cell adhesion mediated by integrin (GO:0033634), podocyte development (GO:0072015), epithelial tube formation (GO:0072175), regulation of cell-cell adhesion (GO:0022407)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (17): ruffle (GO:0001726), obsolete extracellular space (GO:0005615), nucleolus (GO:0005730), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), lamellipodium (GO:0030027), filopodium (GO:0030175), microvillus membrane (GO:0031528), centriolar satellite (GO:0034451), slit diaphragm (GO:0036057), membrane raft (GO:0045121), extracellular exosome (GO:0070062), microvillus (GO:0005902), membrane (GO:0016020), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of cell adhesion	2
cell-cell adhesion	2
cell leading edge	2
plasma membrane bounded cell projection	2
actin-based cell projection	2
cellular process	1
cell adhesion	1
negative regulation of cellular process	1
cell motility	1
negative regulation of cell adhesion	1
regulation of cell-cell adhesion	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
microvillus assembly	1
regulation of microvillus organization	1
regulation of plasma membrane bounded cell projection assembly	1
positive regulation of cell-cell adhesion	1
positive regulation of cell adhesion mediated by integrin	1
cell-cell adhesion mediated by integrin	1
regulation of cell-cell adhesion mediated by integrin	1
podocyte differentiation	1
glomerular epithelial cell development	1
tube formation	1
epithelial tube morphogenesis	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
microvillus	1
cell projection membrane	1
centrosome	1

Protein interactions and networks

STRING

2434 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PODXL	EZR	P15311	992
PODXL	NHERF1	O14745	957
PODXL	NHERF2	Q15599	954
PODXL	NPHS1	O60500	925
PODXL	SYNPO	Q8N3V7	921
PODXL	SELL	P14151	885
PODXL	NPHS2	Q9NP85	870
PODXL	RAB35	Q15286	807
PODXL	CD34	P28906	801
PODXL	GNE	Q9Y223	769
PODXL	WT1	P19544	767
PODXL	ACTN4	O43707	738
PODXL	PDPN	Q86YL7	694
PODXL	EMCN	Q9ULC0	684
PODXL	RUFY1	Q96T51	675

IntAct

180 interactions, top by confidence:

A	B	Type	Score
PODXL	NHERF2	psi-mi:“MI:0915”(physical association)	0.770
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
PODXL	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RHPN1	PODXL	psi-mi:“MI:0914”(association)	0.690
PODXL	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.690
FCN1	POTEF	psi-mi:“MI:0914”(association)	0.530
MRAP2	GOLIM4	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
PODXL	HSPA12A	psi-mi:“MI:0914”(association)	0.530
MRAP2	PODXL	psi-mi:“MI:0914”(association)	0.530
CCR6	PODXL	psi-mi:“MI:0914”(association)	0.530
GPRC5B	STXBP3	psi-mi:“MI:0914”(association)	0.530
HSPA12B	EEF2K	psi-mi:“MI:0914”(association)	0.530
PODXL	IQGAP1	psi-mi:“MI:0403”(colocalization)	0.520
PODXL	IQGAP1	psi-mi:“MI:0915”(physical association)	0.520
IQGAP1	PODXL	psi-mi:“MI:2364”(proximity)	0.520
SELL	PODXL	psi-mi:“MI:0407”(direct interaction)	0.440
PODXL	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
PODXL	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (127): PODXL (Affinity Capture-RNA), PODXL (Affinity Capture-MS), PODXL (Affinity Capture-MS), PODXL (Affinity Capture-MS), PODXL (Affinity Capture-MS), PODXL (Affinity Capture-MS), PODXL (Proximity Label-MS), PODXL (Affinity Capture-MS), PODXL (Affinity Capture-MS), PODXL (Affinity Capture-MS), PODXL (Affinity Capture-MS), PODXL (Affinity Capture-MS), PODXL (Affinity Capture-MS), HSPA12A (Affinity Capture-MS), PODXL (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8Y7Y5, A1KXC4, A6QLF8, J3KML8, O00592, O35188, O55145, O57604, P06484, P07141, P13838, P14220, P15702, P16150, P18827, P20934, P26260, P34740, P47951, P59647, P78423, P97808, Q08DZ5, Q1ECS6, Q28270, Q28645, Q29RT9, Q3MIW9, Q3TNW5, Q52S86, Q58Y74, Q5RAF8, Q62170, Q64314, Q6MG22, Q6P9X9, Q6UWI2, Q6UXF1, Q86YL7, Q8BHE4

Diamond homologs: O00592, O57604, Q04864, Q28645, Q52S86, Q8CAE9, Q9NZ53, Q9R0M4, Q9WTQ2, O73630, P01125, P01126, P15307, P15330, P16236, P19838, P25799, P51509, P51510, P98149, P98150, P98152, Q00653, Q01201, Q04206, Q04207, Q04861, Q04863, Q04865, Q63369, Q6F3J0, Q7TQN4, Q94527, Q9NV72, Q9WTK5, Q9Y2Z0, Q3ZCU0, Q6UX73, Q6ZUF6, Q7JQ07

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
WT1	“up-regulates quantity by expression”	PODXL	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 126 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
Ras activation upon Ca2+ influx through NMDA receptor	5	35.7×	1e-05
Unblocking of NMDA receptors, glutamate binding and activation	5	34.0×	1e-05
Negative regulation of NMDA receptor-mediated neuronal transmission	5	34.0×	1e-05
Assembly and cell surface presentation of NMDA receptors	10	31.7×	6e-11
Dopamine Neurotransmitter Release Cycle	5	31.0×	2e-05
Long-term potentiation	5	29.7×	2e-05
Neurexins and neuroligins	11	27.1×	5e-11
Protein-protein interactions at synapses	7	23.2×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	55.1×	2e-14
protein localization to synapse	6	39.6×	1e-06
receptor clustering	7	37.7×	1e-07
regulation of postsynaptic membrane neurotransmitter receptor levels	8	34.2×	2e-08
establishment of cell polarity	5	16.5×	9e-04
protein-containing complex assembly	11	10.8×	1e-06
cell-cell adhesion	10	8.8×	2e-05
chemical synaptic transmission	10	6.7×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	109
Likely benign	82
Benign	46

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1404663	NM_001018111.3(PODXL):c.888_889delinsTT (p.Gln297Ter)	Pathogenic
2026207	NM_001018111.3(PODXL):c.1185C>A (p.Cys395Ter)	Pathogenic
2980973	NM_001018111.3(PODXL):c.568C>T (p.Arg190Ter)	Pathogenic
3643770	NM_001018111.3(PODXL):c.176dup (p.Asp59fs)	Pathogenic
4701568	NM_001018111.3(PODXL):c.706+1G>A	Likely pathogenic

SpliceAI

1511 predictions. Top by Δscore:

Variant	Effect	Δscore
7:131504504:CGCTG:C	acceptor_gain	1.0000
7:131504505:GCTG:G	acceptor_loss	1.0000
7:131504506:CTG:C	acceptor_gain	1.0000
7:131504507:TG:T	acceptor_gain	1.0000
7:131504507:TGCT:T	acceptor_loss	1.0000
7:131504508:GCTAG:G	acceptor_loss	1.0000
7:131504509:C:CC	acceptor_gain	1.0000
7:131504510:T:A	acceptor_loss	1.0000
7:131504514:G:C	acceptor_gain	1.0000
7:131504514:G:GC	acceptor_gain	1.0000
7:131505863:CTTAC:C	donor_loss	1.0000
7:131505864:TTACC:T	donor_loss	1.0000
7:131505865:TACCT:T	donor_loss	1.0000
7:131505866:A:AC	donor_gain	1.0000
7:131505866:A:T	donor_loss	1.0000
7:131505867:C:CC	donor_gain	1.0000
7:131506032:CTGC:C	acceptor_gain	1.0000
7:131506033:TGCC:T	acceptor_loss	1.0000
7:131506037:T:C	acceptor_loss	1.0000
7:131506040:A:C	acceptor_gain	1.0000
7:131506258:ACCT:A	donor_gain	1.0000
7:131506259:CCTC:C	donor_gain	1.0000
7:131506261:T:TA	donor_gain	1.0000
7:131506322:C:CC	acceptor_gain	1.0000
7:131506575:TCA:T	donor_loss	1.0000
7:131506576:CA:C	donor_loss	1.0000
7:131506577:A:AC	donor_gain	1.0000
7:131506577:AC:A	donor_loss	1.0000
7:131506578:C:CA	donor_gain	1.0000
7:131506578:CT:C	donor_gain	1.0000

AlphaMissense

3592 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:131504376:A:G	W538R	1.000
7:131504376:A:T	W538R	1.000
7:131504450:A:G	L513P	1.000
7:131504458:G:C	N510K	1.000
7:131504458:G:T	N510K	1.000
7:131504462:T:A	D509V	1.000
7:131504462:T:G	D509A	1.000
7:131504374:C:A	W538C	0.999
7:131504374:C:G	W538C	0.999
7:131504456:G:T	P511Q	0.999
7:131504457:G:A	P511S	0.999
7:131504462:T:C	D509G	0.999
7:131504463:C:G	D509H	0.999
7:131504466:G:C	H508D	0.999
7:131504473:A:C	N505K	0.999
7:131504473:A:T	N505K	0.999
7:131504474:T:A	N505I	0.999
7:131504489:A:G	L500P	0.999
7:131505926:A:T	L474H	0.999
7:131505945:A:G	C468R	0.999
7:131504315:A:G	L558P	0.998
7:131504325:C:G	D555H	0.998
7:131504369:A:T	V540D	0.998
7:131504450:A:T	L513Q	0.998
7:131504457:G:T	P511T	0.998
7:131504460:T:C	N510D	0.998
7:131504461:G:C	D509E	0.998
7:131504461:G:T	D509E	0.998
7:131504465:T:G	H508P	0.998
7:131504471:C:A	G506V	0.998

dbSNP variants (sampled 300 via entrez): RS1000216709 (7:131507558 C>A), RS1000252757 (7:131534549 T>G), RS1000256155 (7:131516071 G>A), RS1000275458 (7:131513687 G>A), RS1000343337 (7:131528594 C>T), RS1000360790 (7:131544418 C>T), RS1000367281 (7:131504187 T>C), RS1000375659 (7:131542049 C>G,T), RS1000421114 (7:131550124 T>C,G), RS1000442174 (7:131502536 C>T), RS1000467761 (7:131538990 C>T), RS1000469567 (7:131522335 C>T), RS1000550137 (7:131546267 G>A), RS1000609661 (7:131512422 G>C), RS1000639507 (7:131556274 G>A)

Disease associations

OMIM: gene MIM:602632 | disease phenotypes: MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
nephrotic syndrome	Strong	Autosomal dominant
young-onset Parkinson disease	Supportive	Autosomal recessive
atypical juvenile parkinsonism	Supportive	Autosomal recessive
juvenile-onset Parkinson disease	Limited	Autosomal recessive

Mondo (6): late-onset Parkinson disease (MONDO:0008199), nephrotic syndrome (MONDO:0005377), young-onset Parkinson disease (MONDO:0017279), focal segmental glomerulosclerosis (MONDO:0100313), atypical juvenile parkinsonism (MONDO:0018321), juvenile-onset Parkinson disease (MONDO:0000828)

Orphanet (2): Hereditary late-onset Parkinson disease (Orphanet:411602), Young-onset Parkinson disease (Orphanet:2828)

HPO phenotypes

74 total (30 of 74 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000338	Hypomimic face
HP:0000551	Color vision defect
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000736	Short attention span
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001621	Weak voice
HP:0001761	Pes cavus
HP:0001943	Hypoglycemia
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002019	Constipation
HP:0002049	Proximal renal tubular acidosis
HP:0002063	Rigidity

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002539_69	Schizophrenia	4.000000e-08
GCST003538_4	Alcohol dependence symptom count	1.000000e-08
GCST004143_2	Hypertension	4.000000e-06
GCST005588_35	Idiopathic dilated cardiomyopathy	3.000000e-06
GCST007094_203	Diastolic blood pressure	2.000000e-09
GCST007095_33	Systolic blood pressure	2.000000e-06
GCST007095_34	Systolic blood pressure	5.000000e-06
GCST007099_138	Systolic blood pressure	2.000000e-09
GCST007267_326	Systolic blood pressure	3.000000e-11
GCST007269_220	Pulse pressure	2.000000e-09
GCST007930_79	Medication use (agents acting on the renin-angiotensin system)	4.000000e-08
GCST012490_158	Femur bone mineral density x serum urate levels interaction	3.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007835	alcohol dependence measurement
EFO:0009094	idiopathic dilated cardiomyopathy
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004531	urate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, increases mutagenesis, affects methylation, decreases expression	5
Aflatoxin B1	affects expression, increases expression, increases methylation	4
methylmercuric chloride	affects cotreatment, decreases expression, increases expression	3
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	3
Arsenic Trioxide	affects expression, decreases expression	3
Air Pollutants	increases abundance, increases expression, decreases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
Valproic Acid	affects cotreatment, increases expression, affects expression	3
Particulate Matter	decreases expression, increases abundance	3
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	increases expression, affects cotreatment	2
Calcitriol	increases expression, affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases expression, increases expression	2
Tretinoin	decreases expression	2
Cadmium Chloride	decreases expression, decreases methylation, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
sotorasib	affects cotreatment, decreases expression	1
chloroacetaldehyde	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
glycidyl methacrylate	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1

Cellosaurus cell lines

15 cell lines: 9 cancer cell line, 6 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1E0	Abcam HCT 116 PODXL KO	Cancer cell line	Male
CVCL_B2BB	Abcam HeLa PODXL KO	Cancer cell line	Female
CVCL_C6JC	CHO hPCLP1 clone 12C	Spontaneously immortalized cell line	Female
CVCL_D2TP	PDIS-13	Cancer cell line	Female
CVCL_D2TQ	Lec1/PODXL	Spontaneously immortalized cell line	Female
CVCL_D2TR	Lec13/PODXL	Spontaneously immortalized cell line	Female
CVCL_D2TS	Lec2/PODXL	Spontaneously immortalized cell line	Female
CVCL_D2TT	Lec8/PODXL	Spontaneously immortalized cell line	Female
CVCL_D2TU	LN229/PODXL	Cancer cell line	Female
CVCL_D2TV	LN229/ectodomain-PODXL	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT01129557	PHASE4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462	PHASE4	WITHDRAWN	Acthar for Treatment of Post-transplant FSGS
NCT02585804	PHASE4	COMPLETED	Treating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046	PHASE4	COMPLETED	Acthar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
NCT07015671	PHASE3	COMPLETED	Bioavailability and Bioequivalence Study of ER Torsemide and Spironolactone FDC Tablet in Healthy Subjects
NCT01164098	PHASE3	TERMINATED	Rituximab to Prevent Recurrence of Proteinuria
NCT02683889	PHASE3	COMPLETED	Use of Acthar in Patients With FSGS That Will be Undergoing Renal Transplantation
NCT03298698	PHASE3	UNKNOWN	Efficacy of Rituximab in Comparison to Continued Corticosteroid Treatment in Idiopathic Nephrotic Syndrome
NCT03493685	PHASE3	COMPLETED	Study of Sparsentan in Patients With Primary Focal Segmental Glomerulosclerosis (FSGS)
NCT05183646	PHASE3	RECRUITING	A Study of the Efficacy and Safety of DMX-200 in Patients With FSGS Who Are Receiving an ARB