PKP3

Summary

PKP3 (plakophilin 3, HGNC:9025) is a protein-coding gene on chromosome 11p15.5, encoding Plakophilin-3 (Q9Y446). A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This protein may act in cellular desmosome-dependent adhesion and signaling pathways. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 11187 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 224 total
• Phenotypes (HPO): 2
• MANE Select transcript: NM_007183

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9025
Approved symbol	PKP3
Name	plakophilin 3
Location	11p15.5
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000184363
Ensembl biotype	protein_coding
OMIM	605561
Entrez	11187

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000331563, ENST00000524646, ENST00000525642, ENST00000526971, ENST00000527442, ENST00000528036, ENST00000530695, ENST00000531857, ENST00000533069, ENST00000533249, ENST00000534401, ENST00000895790

RefSeq mRNA: 2 — MANE Select: NM_007183 NM_001303029, NM_007183

CCDS: CCDS7695

Canonical transcript exons

ENST00000331563 — 13 exons

Exon	Start	End
ENSE00001314134	394209	394524
ENSE00002196598	396814	397445
ENSE00003654379	396608	396687
ENSE00004026138	399967	400141
ENSE00004026139	404534	404908
ENSE00004026140	403943	404135
ENSE00004026141	404236	404323
ENSE00004026142	400334	400451
ENSE00004026143	398992	399196
ENSE00004026144	403078	403263
ENSE00004026145	403618	403771
ENSE00004026146	400535	400705
ENSE00004026147	397539	397662

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 99.20.

FANTOM5 (CAGE): breadth broad, TPM avg 9.6195 / max 281.2598, expressed in 617 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112195	6.9339	538
112194	0.9561	348
112191	0.8794	81
112196	0.3183	189
112193	0.2219	110
112190	0.1895	61
112197	0.0972	24
112192	0.0232	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.20	gold quality
skin of abdomen	UBERON:0001416	98.47	gold quality
skin of leg	UBERON:0001511	98.15	gold quality
esophagus mucosa	UBERON:0002469	98.11	gold quality
pharyngeal mucosa	UBERON:0000355	97.54	gold quality
zone of skin	UBERON:0000014	97.48	gold quality
penis	UBERON:0000989	97.30	gold quality
upper arm skin	UBERON:0004263	96.87	gold quality
mucosa of transverse colon	UBERON:0004991	96.69	gold quality
ileal mucosa	UBERON:0000331	95.61	gold quality
nipple	UBERON:0002030	95.46	gold quality
tongue squamous epithelium	UBERON:0006919	95.35	gold quality
mammalian vulva	UBERON:0000997	95.20	gold quality
gingiva	UBERON:0001828	95.17	gold quality
oral cavity	UBERON:0000167	95.11	gold quality
gingival epithelium	UBERON:0001949	94.04	gold quality
endometrium epithelium	UBERON:0004811	93.63	gold quality
body of tongue	UBERON:0011876	93.36	gold quality
nasal cavity epithelium	UBERON:0005384	93.27	gold quality
upper leg skin	UBERON:0004262	93.25	gold quality
cervix epithelium	UBERON:0004801	92.71	gold quality
duodenum	UBERON:0002114	92.58	gold quality
mouth mucosa	UBERON:0003729	92.34	gold quality
minor salivary gland	UBERON:0001830	91.70	gold quality
tongue	UBERON:0001723	91.21	gold quality
saliva-secreting gland	UBERON:0001044	90.47	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.29	gold quality
epithelium of esophagus	UBERON:0001976	90.19	gold quality
skin of hip	UBERON:0001554	90.04	gold quality
right uterine tube	UBERON:0001302	89.96	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	215.91
E-MTAB-8410	yes	23.16
E-ANND-3	yes	9.33
E-CURD-53	no	144.51

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
DSP	Activation
PKP2	Activation

Upstream regulators (CollecTRI, top): PKP1, ZEB1

miRNA regulators (miRDB)

7 targeting PKP3, 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-6752-3P	99.72	66.71	1587
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-4529-5P	96.74	65.77	569
HSA-MIR-4749-3P	96.40	66.24	798

Literature-anchored findings (GeneRIF, showing 31)

• PKP3, whose desmosomal expression and protein interactions are broader than those of PKP1 and -2, is a unique multiprotein binding element in many epithelial desmosomes. (PMID:12707304)
• Cytoplasmic PKP3 is constitutively associated with RNA-binding proteins and indicate an involvement in processes of translation and RNA metabolism. (PMID:16407409)
• The transcriptional repression of PKP3 by ZEB1 contributes to ZEB1-mediated disintegration of intercellular adhesion and epithelial to mesenchymal transition. (PMID:17391671)
• plakophilin3 loss leads to a decrease in cell-cell adhesion leading to the stimulation of neoplastic progression and metastasis (PMID:18729189)
• qRT-PCR assay targeted to plakophilin 3 and anterior gradient-2 mRNAs might be helpful to detect circulating tumor cells in patients with gastrointestinal cancer. (PMID:18801625)
• both loss of PKP1 and up-regulation of PKP3 expression are biologically important events in prostate cancer and are associated with a more aggressive phenotype (PMID:20348237)
• PKP3 mRNA can be used as a marker of subclinical disease in gastrointestinal cancer and thus holds potential clinical relevance as a predictor for disease outcome (PMID:20501752)
• plakoglobin and E-cadherin recruit plakophilin3 to the cell border to initiate desmosome formation (PMID:20859650)
• loss of PKP3 expression during gastric adenocarcinoma progression may indicate an invasive phenotype. (PMID:21194493)
• In breast cancer, compared with normal tissue, PKP1 and PKP2 expressions were indifferent (P > 0.05), but PKP3 expression was significantly increased (PMID:21947748)
• These results demonstrate a strong association of single-nucleotide polymorphisms in the PKP3-SIGIRR-TMEM16J gene region and tuberculosis in discovery and validation cohorts. (PMID:22223854)
• Plakophilin3 loss leads to an increase in PRL3 levels promoting K8 dephosphorylation, which is required for transformation and metastasis. (PMID:22701666)
• stratifin plays a role in regulating plakophilin-3 incorporation into the desmosomal plaque by forming a plakophilin-3 stratifin complex in the cytosol and thereby affecting desmosome dynamics in squamous epithelial cells. (PMID:24124604)
• The study describes a new protein variant of the human PKP3 gene, namely PKP3b, which differs from the published PKP3a only at the amino-terminus by the splicing in of the newly identified exon 1b. (PMID:24178805)
• Pemphigus vulgaris autoimmune globulin induces Src-dependent tyrosine-phosphorylation of PKP3 and its detachment from DSG3. (PMID:24328683)
• These findings reveal Pkp3 as a coordinator of desmosome and adherens junction assembly and maturation through its functional association with Rap1. (PMID:25208567)
• cytoplasmic PKP1/3 are components of mRNA ribonucleoprotein particles and act as posttranscriptional regulators of gene expression. (PMID:25225333)
• reactive oxygen species (ROS) trigger the c-Src kinase-mediated tyrosine (Tyr)-195 phosphorylation of PKP3. (PMID:25501895)
• The results suggest that MMP7 over-expression may be one of the mechanisms by which PKP3 loss leads to increased cell invasion and tumor formation. (PMID:25875355)
• Data suggest juxtamembrane regions/domains of desmocollin-2 (DSC2), plakophilin 2 (PKP2), and plakophilin 3 (PKP3) are involved in desmosome formation in epithelial cells; DSC2 participates in desmosome formation in absence of desmoglein 2 (DSG2). (PMID:25972099)
• Children with low 25-hydroxyvitamin D and TMEM16J rs7111432-AA or PKP3 rs10902158-GG polymorphisms were at increased risk for tuberculosis or death. (PMID:26872154)
• PKP3 overexpression increases the stability of other desmosomal proteins independently of the increase in DSC2 levels and regulates desmosome formation and stability by a multimodal mechanism affecting transcription, protein stability and cell border localization of desmosomal proteins. (PMID:29146182)
• 14-3-3sigma (also known as stratifin, encoded by SFN) interacted preferentially with S285-phosphorylated PKP3 to promote its accumulation at tricellular contact sites, leading to stable desmosomes. (PMID:29678907)
• plakophilin 3 appears to be involved in tumor invasion in malignant mesothelioma (PMID:29722422)
• PKP3 loss leads to an increase in invasion, tumor formation and metastasis and these phenotypes were dependent on the increase in LCN2 expression. (PMID:29803740)
• Nasopharyngeal carcinoma (NPC) tissues display a significant high miR-149 and low PKP3 expressions indicating that both play an important role in NPC metastasis. Downregulation of miR-149 resulting in the increment of PKP3 expression. Also, N,N’-dinitrosopiperazine (DNP)-mediated PKP3 decrease was eliminated by miR-149 in NPC cells. This suggests that DNP may reduce PKP3 expression through upregulating miR-149. (PMID:30144176)
• The result of this study PKP3 as the oncogene candidate and a potential target for the treatment of ovarian cancer. (PMID:30527804)
• A catenin of the plakophilin-subfamily, Pkp3, responds to canonical-Wnt pathway components and signals. (PMID:34058472)
• Plakophilin 3 and Par3 facilitate desmosomes’ association with the apical junctional complex. (PMID:34260281)
• Disease-related blood-based differential methylation in cystic fibrosis and its representation in lung cancer revealed a regulatory locus in PKP3 in lung epithelial cells. (PMID:34415821)
• Role and function of plakophilin 3 in cancer progression and skin disease. (PMID:38048779)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pkp3a	ENSDARG00000051861
danio_rerio	pkp3b	ENSDARG00000079438
mus_musculus	Pkp3	ENSMUSG00000054065
rattus_norvegicus	Pkp3	ENSRNOG00000015152
drosophila_melanogaster	p120ctn	FBGN0260799
caenorhabditis_elegans		WBGENE00002175

Paralogs (6): PKP2 (ENSG00000057294), PKP1 (ENSG00000081277), ARVCF (ENSG00000099889), PKP4 (ENSG00000144283), CTNND2 (ENSG00000169862), CTNND1 (ENSG00000198561)

Protein

Protein identifiers

Plakophilin-3 — Q9Y446 (reviewed: Q9Y446)

All UniProt accessions (5): E9PK71, E9PQ15, E9PRW6, Q9Y446, H0YEY5

UniProt curated annotations — full annotation on UniProt →

Function. A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. Required for the localization of DSG2, DSP and PKP2 to mature desmosome junctions. May also play a role in the maintenance of DSG3 protein abundance in keratinocytes. Required for the formation of DSP-containing desmosome precursors in the cytoplasm during desmosome assembly. Also regulates the accumulation of CDH1 to mature desmosome junctions, via cAMP-dependent signaling and its interaction with activated RAP1A. Positively regulates the stabilization of PKP2 mRNA and therefore protein abundance, via its interaction with FXR1, may also regulate the protein abundance of DSP via the same mechanism. May also regulate the protein abundance of the desmosome component PKP1. Required for the organization of desmosome junctions at intercellular borders between basal keratinocytes of the epidermis, as a result plays a role in maintenance of the dermal barrier and regulation of the dermal inflammatory response. Required during epidermal keratinocyte differentiation for cell adherence at tricellular cell-cell contacts, via regulation of the timely formation of adherens junctions and desmosomes in a calcium-dependent manner, and may also play a role in the organization of the intracellular actin fiber belt. Acts as a negative regulator of the inflammatory response in hematopoietic cells of the skin and intestine, via modulation of proinflammatory cytokine production. Important for epithelial barrier maintenance in the intestine to reduce intestinal permeability, thereby plays a role in protection from intestinal-derived endotoxemia. Required for the development of hair follicles, via a role in the regulation of inner root sheaf length, correct alignment and anterior-posterior polarity of hair follicles. Promotes proliferation and cell-cycle G1/S phase transition of keratinocytes. Promotes E2F1-driven transcription of G1/S phase promoting genes by acting to release E2F1 from its inhibitory interaction with RB1, via sequestering RB1 and CDKN1A to the cytoplasm and thereby increasing CDK4- and CDK6-driven phosphorylation of RB1. May act as a scaffold protein to facilitate MAPK phosphorylation of RPS6KA protein family members and subsequently promote downstream EGFR signaling. May play a role in the positive regulation of transcription of Wnt-mediated TCF-responsive target genes.

Subunit / interactions. Found in a complex composed of CDH1, RAP1A and PKP3; PKP3 acts as a scaffold protein within the complex, the complex is required for CDH1 localization to mature desmosome cell junctions. Interacts with FXR1; the interaction facilitates the binding of PKP3 to PKP2 mRNA. Interacts (via ARM repeats) with GSK3B; the interaction may be involved in PKP3 protein degradation. Interacts with hyperphosphorylated and hypophosphorylated RB1; the interaction inhibits RB1 interaction with and repression of the transcription factor E2F1, potentially via sequestering RB1 to the cytoplasm. Interacts with CDKN1A; the interaction sequesters CDKN1A to the cytoplasm thereby repressing its role as an inhibitor of CDK4- and CDK6-driven RB1 phosphorylation. Interacts (via N-terminus) with SFN; the interaction maintains the cytoplasmic pool of PKP3, facilitates PKP3 exchange at desmosomes and restricts PKP3 localization to existing desmosome cell junctions. Interacts (via N-terminus) with JUP; the interaction is required for PKP3 localization to desmosome cell-cell junctions.

Subcellular location. Nucleus. Cell junction. Desmosome. Cytoplasm. Cell membrane. Adherens junction Cell junction. Cytoplasm Cell junction.

Tissue specificity. Expressed in the epidermis of the skin, in squamous non-cornifying epithelial cells in the vagina, single layer epithelia of the duodenum and pancreas acini and non-epithelial dendritic reticulum cells of lymph node follicles (at protein level). Expressed in the oral cavity mucosa, epidermis and small intestine epithelium (at protein level). Expressed in the oral cavity mucosa and epithelial cells of the crypts and villi in the small intestine (at protein level). Expressed in the epidermis with more abundant expression found in the basal and low spinous cells (at protein level).

Post-translational modifications. Phosphorylated at Ser-285 when localized to the cytoplasm, PKP3 at desmosome cell junctions is not phosphorylated. Phosphorylation at Try-195 by SRC is induced by reactive oxygen species and potentially acts as a release mechanism from desmosome cell-cell junctions.

Miscellaneous. Poorly differentiated, high Gleason grade prostate adenocarcinomas show an increase in phosphorylation at Tyr-195, potentially indicating a role for SRC-driven phosphorylation of PKP3 in the dedifferentiation of prostate tumor cells.

Similarity. Belongs to the beta-catenin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y446-1	PKP3a	yes
Q9Y446-2	PKP3b

RefSeq proteins (2): NP_001289958, NP_009114* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR028435	Plakophilin/d_Catenin	Family

Pfam: PF00514

UniProt features (31 total): modified residue 13, repeat 8, region of interest 4, sequence conflict 2, chain 1, site 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y446-F1	69.24	0.50

Functional residue map

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

Catalytic / active sites (1): 285 (interacts with sfn)

Post-translational modifications (13): 81, 123, 180, 183, 195, 238, 240, 250, 261, 285, 313, 314, 331

Mutagenesis-validated functional residues (1):

Position	Phenotype
285	abolishes interaction with sfn.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6805567	Keratinization
R-HSA-6809371	Formation of the cornified envelope

MSigDB gene sets: 228 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, RORA1_01, JAEGER_METASTASIS_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HAIR_CYCLE, GGGTGGRR_PAX4_03, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_REGULATION_OF_HAIR_FOLLICLE_DEVELOPMENT

GO Biological Process (16): desmosome assembly (GO:0002159), regulation of cytokine production involved in immune response (GO:0002718), desmosome organization (GO:0002934), epithelial structure maintenance (GO:0010669), positive regulation of cell-cell adhesion (GO:0022409), actin cytoskeleton organization (GO:0030036), positive regulation of cell adhesion (GO:0045785), regulation of hair follicle development (GO:0051797), protein localization to plasma membrane (GO:0072659), epithelial cell-cell adhesion (GO:0090136), cell-cell adhesion (GO:0098609), negative regulation of mRNA catabolic process (GO:1902373), positive regulation of cell cycle G1/S phase transition (GO:1902808), positive regulation of protein localization (GO:1903829), cell adhesion (GO:0007155), regulation of gene expression (GO:0010468)

GO Molecular Function (7): RNA binding (GO:0003723), enzyme binding (GO:0019899), alpha-catenin binding (GO:0045294), cadherin binding (GO:0045296), cell adhesion molecule binding (GO:0050839), cadherin binding involved in cell-cell adhesion (GO:0098641), protein binding (GO:0005515)

GO Cellular Component (11): cornified envelope (GO:0001533), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), adherens junction (GO:0005912), cell junction (GO:0030054), desmosome (GO:0030057), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Developmental Biology	1
Keratinization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell-cell adhesion	3
protein binding	3
cell adhesion	2
cell-cell junction	2
desmosome organization	1
cell-cell junction assembly	1
regulation of cytokine production	1
cytokine production involved in immune response	1
regulation of production of molecular mediator of immune response	1
cell-cell junction organization	1
tissue homeostasis	1
regulation of cell-cell adhesion	1
positive regulation of cell adhesion	1
cytoskeleton organization	1
actin filament-based process	1
regulation of cell adhesion	1
positive regulation of cellular process	1
hair follicle development	1
regulation of hair cycle	1
regulation of multicellular organismal development	1
protein localization to membrane	1
protein localization to cell periphery	1
mRNA catabolic process	1
positive regulation of gene expression	1
regulation of mRNA catabolic process	1
negative regulation of RNA catabolic process	1
negative regulation of mRNA metabolic process	1
cell cycle G1/S phase transition	1
positive regulation of cell cycle phase transition	1
regulation of cell cycle G1/S phase transition	1
intracellular protein localization	1
regulation of protein localization	1
positive regulation of biological process	1
cellular process	1
gene expression	1
regulation of macromolecule biosynthetic process	1
nucleic acid binding	1
cell adhesion molecule binding	1
cadherin binding	1

Protein interactions and networks

STRING

1280 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PKP3	FXR1	P51114	918
PKP3	DSG3	P32926	893
PKP3	DSG1	Q02413	802
PKP3	PABPC1	P11940	799
PKP3	DSP	P15924	787
PKP3	DSC3	Q14574	786
PKP3	DSG2	Q14126	752
PKP3	DSC2	Q02487	751
PKP3	G3BP1	Q13283	727
PKP3	PKP1	Q13835	644
PKP3	SFN	P31947	596
PKP3	PKP2	Q99959	580
PKP3	ANO9	A1A5B4	571
PKP3	JUP	P14923	558
PKP3	PPL	O60437	531

IntAct

128 interactions, top by confidence:

A	B	Type	Score
RBM8A	CASC3	psi-mi:“MI:0914”(association)	0.900
MAPK14	RPS6KA4	psi-mi:“MI:0914”(association)	0.870
OAZ3	AZIN1	psi-mi:“MI:0914”(association)	0.800
SMARCD1	ARID1A	psi-mi:“MI:0914”(association)	0.790
KIF3A	KIF3C	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
IQUB	PKP3	psi-mi:“MI:0915”(physical association)	0.560
PKP3	GFAP	psi-mi:“MI:0915”(physical association)	0.560
MAS1	POTEF	psi-mi:“MI:0914”(association)	0.530
CCDC51	TGM5	psi-mi:“MI:0914”(association)	0.530
RBM24	PPL	psi-mi:“MI:0914”(association)	0.530
GDF5	SERPINB7	psi-mi:“MI:0914”(association)	0.530
CPLX3	CIAO1	psi-mi:“MI:0914”(association)	0.530
B3GALNT1	DUSP14	psi-mi:“MI:0914”(association)	0.530
CFAP210	DUSP14	psi-mi:“MI:0914”(association)	0.530
SYT16	DUSP14	psi-mi:“MI:0914”(association)	0.530
LACC1	DUSP14	psi-mi:“MI:0914”(association)	0.530
NSMAF	DUSP14	psi-mi:“MI:0914”(association)	0.530
RHOBTB2	DUSP14	psi-mi:“MI:0914”(association)	0.530
FBXL4	DUSP14	psi-mi:“MI:0914”(association)	0.530
ELMOD1	LDHC	psi-mi:“MI:0914”(association)	0.530

BioGRID (187): PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS), PKP3 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I3QA39, A2A6T1, A2A9T0, A2AHG0, A5PKL7, A6NKD9, A7MCY6, B4F7F3, D3ZD05, E9Q6B2, F1MRK3, G3V735, O00192, O60299, O75069, O75145, P60469, P98203, Q08DQ0, Q0P485, Q0V989, Q1LZH7, Q2HJJ0, Q2TBQ9, Q3LUD4, Q4ACU6, Q4V872, Q5R8E2, Q5SP85, Q63ZY3, Q6DHL7, Q6NZT2, Q6P597, Q80W04, Q86X02, Q8BX02, Q8K1Q4, Q8K371, Q8R361, Q8VHK2

Diamond homologs: B0BF33, F1M7L9, O35116, O35927, P97350, Q08DQ0, Q13835, Q28161, Q68FH0, Q99569, Q99959, Q9CQ73, Q9QY23, Q9UQB3, Q9Y446, B4F7F3, O00192, O60716, P30999, P98203, Q8AXM9, Q9U308, Q9C9A6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SRC	“up-regulates activity”	PKP3	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	195
Likely benign	12
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1868 predictions. Top by Δscore:

Variant	Effect	Δscore
11:394522:GAG:G	donor_gain	1.0000
11:394525:GTAG:G	donor_loss	1.0000
11:397442:GCGG:G	donor_gain	1.0000
11:397537:A:AG	acceptor_gain	1.0000
11:397538:G:GG	acceptor_gain	1.0000
11:397538:GTTTT:G	acceptor_gain	1.0000
11:399169:G:GT	donor_gain	1.0000
11:399178:C:G	donor_gain	1.0000
11:399191:TCAC:T	donor_gain	1.0000
11:399192:CACAG:C	donor_loss	1.0000
11:399194:CAG:C	donor_loss	1.0000
11:399195:AGGTG:A	donor_loss	1.0000
11:399196:GGTG:G	donor_loss	1.0000
11:399962:TCCAG:T	acceptor_loss	1.0000
11:399964:CA:C	acceptor_loss	1.0000
11:399965:A:AG	acceptor_gain	1.0000
11:399965:AG:A	acceptor_gain	1.0000
11:399965:AGG:A	acceptor_gain	1.0000
11:399966:G:GA	acceptor_gain	1.0000
11:399966:GG:G	acceptor_gain	1.0000
11:399966:GGG:G	acceptor_gain	1.0000
11:399966:GGGA:G	acceptor_gain	1.0000
11:399966:GGGAT:G	acceptor_gain	1.0000
11:400142:G:GA	donor_loss	1.0000
11:400332:A:AG	acceptor_gain	1.0000
11:400333:G:GG	acceptor_gain	1.0000
11:400447:ACAAG:A	donor_loss	1.0000
11:400449:AAGG:A	donor_loss	1.0000
11:400451:GGT:G	donor_loss	1.0000
11:400453:T:A	donor_loss	1.0000

AlphaMissense

5111 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:399086:T:C	L388P	1.000
11:399975:T:A	W428R	1.000
11:399975:T:C	W428R	1.000
11:400141:G:T	R483M	1.000
11:400565:A:G	N533D	1.000
11:400567:C:A	N533K	1.000
11:400567:C:G	N533K	1.000
11:400569:T:C	L534P	1.000
11:400572:C:T	S535F	1.000
11:403242:C:A	N634K	1.000
11:403242:C:G	N634K	1.000
11:397565:C:A	A324E	0.999
11:397568:T:A	V325D	0.999
11:397622:T:A	I343N	0.999
11:397633:T:C	C347R	0.999
11:397635:C:G	C347W	0.999
11:397656:G:C	K354N	0.999
11:397656:G:T	K354N	0.999
11:399084:C:A	N387K	0.999
11:399084:C:G	N387K	0.999
11:399111:G:C	K396N	0.999
11:399111:G:T	K396N	0.999
11:399977:G:C	W428C	0.999
11:399977:G:T	W428C	0.999
11:399978:A:G	N429D	0.999
11:399980:C:A	N429K	0.999
11:399980:C:G	N429K	0.999
11:399982:T:C	L430P	0.999
11:400004:G:C	K437N	0.999
11:400004:G:T	K437N	0.999

dbSNP variants (sampled 300 via entrez): RS1000004966 (11:390982 C>T), RS1000295694 (11:395475 C>A,T), RS1000396690 (11:399224 C>A,G,T), RS1000439916 (11:391123 C>T), RS1000728344 (11:399629 G>A), RS1000864355 (11:395527 G>A,T), RS1000895405 (11:395690 A>G), RS1000899325 (11:394546 G>A), RS1001238623 (11:394439 G>A), RS1001283366 (11:394474 C>A,T), RS1001330209 (11:400380 T>G), RS1001356285 (11:394605 G>A), RS1001405744 (11:391801 C>T), RS1001518770 (11:394785 G>A), RS1001607115 (11:398856 C>A,G)

Disease associations

OMIM: gene MIM:605561 | disease phenotypes:

GenCC curated gene-disease

Mondo (2): neutropenia (MONDO:0001475), lymphopenia (MONDO:0003783)

Orphanet (0):

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0001875	Decreased total neutrophil count
HP:0001888	Decreased total lymphocyte count

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010206_6	Anorectal malformation	3.000000e-16
GCST90002388_530	Lymphocyte count	3.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008231	Lymphopenia	C15.378.243.750.605; C15.378.553.546.605; C20.673.627
D009503	Neutropenia	C15.378.243.750.184.564; C15.378.553.546.184.564

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	4
Valproic Acid	increases expression, increases methylation, affects cotreatment	4
Resveratrol	affects cotreatment, decreases expression	2
Air Pollutants	increases abundance, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	increases expression	1
nickel sulfate	increases expression	1
coumarin	decreases phosphorylation	1
nivalenol	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
celastrol	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	increases expression	1
MT19c compound	decreases expression	1
Temozolomide	affects response to substance	1
Arsenic Trioxide	decreases response to substance	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Calcitriol	increases expression	1
Carmustine	affects response to substance	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2AZ	Abcam HeLa PKP3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00125723	PHASE4	COMPLETED	FIRST - Study of Pegfilgrastim Administered in the First and Subsequent Cycles of Myelosuppressive Chemotherapy
NCT00194857	PHASE4	TERMINATED	Treatment of Anemia and Neutropenia in HIV/HCV Coinfected Patients Treated With Pegylated Interferon and Ribavirin
NCT00257790	PHASE4	COMPLETED	The Tobramycin Study
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00686543	PHASE4	COMPLETED	Oral Posaconazole in High Risk Patients With Gastrointestinal Dysfunction (Study P05115)
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01114165	PHASE4	COMPLETED	Value of the LightCycler® SeptiFast Test MGRADE for the Pathogen Detection in Neutropenic Hematological Patients
NCT01135589	PHASE4	UNKNOWN	Micafungin Prevention Study for Fungal Disease in Child Receiving Allogenic Hematopoietic Stem Cell Transplantation
NCT01571518	PHASE4	UNKNOWN	Prevention of Neutropenia After Using G-CSF With TAC Chemotherapy
NCT02621905	PHASE4	COMPLETED	Steady-State Comparative Bioavailability Study in Prophylaxis Patients of Lozanoc® 50 mg With Sporanox® 100 mg
NCT02967341	PHASE4	UNKNOWN	Blood Draw Validation for Ciprofloxacin Pharmacokinetic Research in Pediatric Cancer Patients
NCT04009941	PHASE4	COMPLETED	Efficacy and Safety of 4.5mg PEG-rhG-CSF Per Cycle in Preventing Neutropenia After Intensive Chemotherapy for Breast Cancer
NCT04904614	PHASE4	COMPLETED	Letermovir Use in Heart Transplant Recipients
NCT05626530	PHASE4	RECRUITING	Letermovir for Secondary Prophylaxis in Solid Organ Transplant Recipients
NCT06145321	PHASE4	ACTIVE_NOT_RECRUITING	Continuous Versus Bolus Administration of G-CSF in Children With Cancer
NCT00001338	PHASE3	COMPLETED	A Prospective, Randomized, Phase III Trial of FLAC (5-Fluorouracil, Leucovorin, Adriamycin, Cytoxan) Chemotherapy With GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) Versus PIXY 321 in Advanced Breast Cancer
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00002658	PHASE3	UNKNOWN	Combination Chemotherapy, Biological Therapy, and Bone Marrow Transplantation in Treating Patients With Acute Myeloid Leukemia
NCT00002719	PHASE3	COMPLETED	Combination Chemotherapy With or Without G-CSF in Treating Older Patients With Acute Myeloid Leukemia
NCT00003739	PHASE3	COMPLETED	Antibiotic Therapy With or Without G-CSF in Treating Children With Neutropenia and Fever Caused by Chemotherapy
NCT00020865	PHASE3	UNKNOWN	Levofloxacin Compared With Cefepime in Treating Cancer Patients With Fever and Neutropenia
NCT00035594	PHASE3	COMPLETED	Pegfilgrastim as Support to Advanced Breast Cancer Patients Receiving Chemotherapy
NCT00044486	PHASE3	COMPLETED	Prophylaxis Trial of Posaconazole Versus Standard Azole Therapy for Neutropenic Patients (Study P01899)
NCT00107081	PHASE3	TERMINATED	Low-risk Fever and Neutropenia in Children With Cancer: Safety and Efficacy of Oral Antibiotics in an Outpatient Setting
NCT00445497	PHASE3	UNKNOWN	Early Hospital Discharge or Standard Inpatient Care in Cancer Patients Receiving Antibiotics for Febrile Neutropenia
NCT00529282	PHASE3	TERMINATED	A Study of Ceftobiprole in Patients With Fever and Neutropenia.
NCT00627393	PHASE3	COMPLETED	Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study)
NCT00770172	PHASE3	COMPLETED	G-CSF in Preventing Neutropenia in Patients With Solid Tumors Who Are Receiving Chemotherapy
NCT00784368	PHASE3	COMPLETED	A Pharmacokinetic Study of JK1211(Itraconazole [Itrizole]) Oral Solution in Participants With Deep Mycosis and Those With Febrile Neutropenia Suspected of Fungal Infection
NCT00806351	PHASE3	TERMINATED	An Evaluation Of The Effectiveness And Safety Of Anidulafungin Compared To Caspofungin For The Treatment Of Serious Fungal Infection Due To Candida In Patients With A Dysfunctional Immune System
NCT00911170	PHASE3	COMPLETED	PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Factor (VEGF) Evaluation Study
NCT01307579	PHASE3	COMPLETED	Caspofungin Versus Fluconazole in Preventing Invasive Fungal Infections (IFI) in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia
NCT01371656	PHASE3	COMPLETED	Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation
NCT01560195	PHASE3	UNKNOWN	A Study of Pegylated rhG-CSF as Support to Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients Receiving Chemotherapy Receiving Chemotherapy
NCT01611051	PHASE3	COMPLETED	A Study Comparing Pegylated rhG-CSF and rhG-CSF as Support to Breast Cancer Patients Receiving Chemotherapy
NCT02238873	PHASE3	UNKNOWN	Pegfilgrastim on Day +3 Compared to Day +1 After Salvage Chemotherapy for Patients With Refractory or Relapsed Aggressive Lymphoma
NCT02414581	PHASE3	COMPLETED	Mouthwash With Chlorhexidine 0.12%/Ethyl Alcohol 7% Compared to Ethyl Alcohol 7%
NCT02643420	PHASE3	COMPLETED	SPI-2012 vs Pegfilgrastim in the Management of Neutropenia in Participants With Breast Cancer With Docetaxel and Cyclophosphamide (ADVANCE)
NCT02872103	PHASE3	COMPLETED	Placebo-controlled Trial of F-627 in Women With Breast Cancer Receiving Myelotoxic Chemotherapy