ZFYVE28

Summary

ZFYVE28 (zinc finger FYVE-type containing 28, HGNC:29334) is a protein-coding gene on chromosome 4p16.3, encoding Lateral signaling target protein 2 homolog (Q9HCC9). Negative regulator of epidermal growth factor receptor (EGFR) signaling.

Enables phosphatidylinositol-3-phosphate binding activity. Involved in negative regulation of epidermal growth factor-activated receptor activity. Located in cytosol and early endosome membrane.

Source: NCBI Gene 57732 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 213 total
• MANE Select transcript: NM_020972

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29334
Approved symbol	ZFYVE28
Name	zinc finger FYVE-type containing 28
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1643, lst-2
Ensembl gene	ENSG00000159733
Ensembl biotype	protein_coding
OMIM	614176
Entrez	57732

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000290974, ENST00000503000, ENST00000504743, ENST00000505421, ENST00000508184, ENST00000508471, ENST00000509171, ENST00000511071, ENST00000514248, ENST00000515169, ENST00000515312

RefSeq mRNA: 6 — MANE Select: NM_020972 NM_001172656, NM_001172657, NM_001172658, NM_001172659, NM_001172660, NM_020972

CCDS: CCDS33942, CCDS54708, CCDS54709, CCDS54710, CCDS54711, CCDS54712

Canonical transcript exons

ENST00000290974 — 13 exons

Exon	Start	End
ENSE00001047417	2320170	2320271
ENSE00001047420	2335705	2335794
ENSE00001047423	2273173	2273289
ENSE00001047424	2271311	2271414
ENSE00001047426	2337407	2337496
ENSE00001047430	2271675	2271779
ENSE00001164269	2269597	2270856
ENSE00001274887	2304289	2305536
ENSE00001274913	2339453	2339655
ENSE00002054772	2418285	2418645
ENSE00003536368	2341478	2341615
ENSE00003555347	2353933	2354073
ENSE00003653574	2274062	2274216

Expression profiles

Bgee: expression breadth ubiquitous, 202 present calls, max score 97.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.1133 / max 268.8098, expressed in 1441 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
51129	3.7090	969
51128	1.5960	476
51119	1.2246	663
51130	0.3152	157
51126	0.0873	39
51125	0.0779	34
51127	0.0778	33
51124	0.0254	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	97.09	gold quality
cerebellar hemisphere	UBERON:0002245	96.86	gold quality
cerebellar cortex	UBERON:0002129	96.75	gold quality
cerebellum	UBERON:0002037	95.88	gold quality
granulocyte	CL:0000094	91.42	gold quality
right frontal lobe	UBERON:0002810	88.98	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.51	gold quality
mucosa of transverse colon	UBERON:0004991	85.73	gold quality
metanephros cortex	UBERON:0010533	85.56	gold quality
anterior cingulate cortex	UBERON:0009835	85.32	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.28	gold quality
transverse colon	UBERON:0001157	84.86	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.82	gold quality
nucleus accumbens	UBERON:0001882	84.33	gold quality
body of stomach	UBERON:0001161	84.27	gold quality
frontal cortex	UBERON:0001870	84.26	gold quality
prefrontal cortex	UBERON:0000451	84.23	gold quality
left adrenal gland cortex	UBERON:0035825	84.14	gold quality
adenohypophysis	UBERON:0002196	83.97	gold quality
caudate nucleus	UBERON:0001873	83.95	gold quality
pituitary gland	UBERON:0000007	83.86	gold quality
small intestine Peyer’s patch	UBERON:0003454	83.85	gold quality
right adrenal gland cortex	UBERON:0035827	83.75	gold quality
neocortex	UBERON:0001950	83.66	gold quality
right adrenal gland	UBERON:0001233	83.65	gold quality
right lobe of thyroid gland	UBERON:0001119	83.60	gold quality
left adrenal gland	UBERON:0001234	83.56	gold quality
sural nerve	UBERON:0015488	83.47	gold quality
lower esophagus mucosa	UBERON:0035834	83.38	gold quality
left lobe of thyroid gland	UBERON:0001120	83.20	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.72

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

67 targeting ZFYVE28, 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-1193	100.00	65.93	529
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-7157-5P	99.66	69.33	1829
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-3915	99.45	68.49	1905
HSA-MIR-519D-5P	99.41	69.30	2057

Literature-anchored findings (GeneRIF, showing 2)

• Study concludes that endosomal localization of Lst2 (ZFYVE28), along with an ability to divert incoming EGFR molecules to degradation in lysosomes, is regulated by ubiquitinylation/deubiquitinylation cycles. (PMID:19460345)
• ZFYVE28 mediates insulin resistance by promoting phosphorylated insulin receptor degradation via increasing late endosomes production. (PMID:37884540)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	zfyve28	ENSDARG00000060430
mus_musculus	Zfyve28	ENSMUSG00000037224
rattus_norvegicus	Zfyve28	ENSRNOG00000014874
drosophila_melanogaster	CG6051	FBGN0039492
drosophila_melanogaster	CG31064	FBGN0051064
caenorhabditis_elegans		WBGENE00003084

Paralogs (13): RUFY3 (ENSG00000018189), ZFYVE16 (ENSG00000039319), SNX29 (ENSG00000048471), ZFYVE26 (ENSG00000072121), RUNDC3B (ENSG00000105784), RUNDC3A (ENSG00000108309), PLEKHM2 (ENSG00000116786), ZFYVE1 (ENSG00000165861), ZFYVE19 (ENSG00000166140), PLEKHF1 (ENSG00000166289), PLEKHF2 (ENSG00000175895), RUFY1 (ENSG00000176783), RUFY2 (ENSG00000204130)

Protein

Protein identifiers

Lateral signaling target protein 2 homolog — Q9HCC9 (reviewed: Q9HCC9)

Alternative names: Zinc finger FYVE domain-containing protein 28

All UniProt accessions (3): Q9HCC9, D6RID3, Q49AA1

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of epidermal growth factor receptor (EGFR) signaling. Acts by promoting EGFR degradation in endosomes when not monoubiquitinated.

Subunit / interactions. Interacts with TRIM3.

Subcellular location. Cytoplasm. Cytosol. Early endosome membrane.

Post-translational modifications. Monoubiquitination at Lys-87 prevents binding to phosphatidylinositol 3-phosphate (PI3P) and localization to early endosome membranes.

Domain organisation. The FYVE-type zinc finger mediates the interaction with phosphatidylinositol 3-phosphate (PI3P) and localization to early endosome membranes when not monoubiquitinated at Lys-87.

Similarity. Belongs to the lst-2 family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q9HCC9-1	1	yes
Q9HCC9-2	2
Q9HCC9-3	3
Q9HCC9-4	4
Q9HCC9-5	5
Q9HCC9-6	6
Q9HCC9-7	7
Q9HCC9-8	8

RefSeq proteins (6): NP_001166127, NP_001166128, NP_001166129, NP_001166130, NP_001166131, NP_066023* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000306	Znf_FYVE	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017455	Znf_FYVE-rel	Domain
IPR043269	FYVE_LST2	Domain
IPR051118	LST-2	Family

Pfam: PF01363

UniProt features (43 total): splice variant 9, binding site 8, sequence conflict 7, modified residue 4, region of interest 4, compositionally biased region 4, sequence variant 2, mutagenesis site 2, chain 1, zinc finger region 1, cross-link 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9F42	ELECTRON MICROSCOPY	3.27
9F43	ELECTRON MICROSCOPY	3.49
9F44	ELECTRON MICROSCOPY	3.68
9F45	ELECTRON MICROSCOPY	3.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCC9-F1	62.45	0.26

Functional residue map

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

Ligand- & substrate-binding residues (8): 823; 826; 839; 842; 847; 850; 869; 872

Post-translational modifications (5): 334, 516, 586, 870, 87

Mutagenesis-validated functional residues (2):

Position	Phenotype
87	abolishes monoubiquitination and promotes localization to early endosomes.
823	abolishes binding to phosphatidylinositol 3-phosphate (pi3p).

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 155 (showing top): GOBP_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_ERBB_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, chr4p16, GOBP_NEGATIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS

GO Biological Process (2): negative regulation of epidermal growth factor-activated receptor activity (GO:0007175), negative regulation of epidermal growth factor receptor signaling pathway (GO:0042059)

GO Molecular Function (4): zinc ion binding (GO:0008270), phosphatidylinositol-3-phosphate binding (GO:0032266), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): cytosol (GO:0005829), early endosome membrane (GO:0031901), cytoplasm (GO:0005737), endosome (GO:0005768), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
epidermal growth factor receptor activity	1
negative regulation of epidermal growth factor receptor signaling pathway	1
negative regulation of protein tyrosine kinase activity	1
negative regulation of signaling receptor activity	1
epidermal growth factor receptor signaling pathway	1
regulation of epidermal growth factor receptor signaling pathway	1
negative regulation of ERBB signaling pathway	1
transition metal ion binding	1
phosphatidylinositol phosphate binding	1
binding	1
cation binding	1
cytoplasm	1
early endosome	1
endosome membrane	1
intracellular anatomical structure	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

590 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZFYVE28	EXD3	Q8N9H8	692
ZFYVE28	RBM46	Q8TBY0	690
ZFYVE28	ZNF678	Q5SXM1	674
ZFYVE28	BOLA3	Q53S33	571
ZFYVE28	FIRRM	Q9NSG2	502
ZFYVE28	SH3RF3	Q8TEJ3	483
ZFYVE28	SLITRK1	Q96PX8	452
ZFYVE28	PPP1R7	Q15435	434
ZFYVE28	EPS8L3	Q8TE67	391
ZFYVE28	ANKRD33B	A6NCL7	378
ZFYVE28	MATCAP2	Q8NCT3	370
ZFYVE28	PRELID1	Q9Y255	370
ZFYVE28	ZNF561	Q8N587	368
ZFYVE28	PARD6G	Q9BYG4	368
ZFYVE28	ZNF696	Q9H7X3	368

IntAct

2 interactions, top by confidence:

A	B	Type	Score
PRNP	ZFYVE28	psi-mi:“MI:0407”(direct interaction)	0.000

BioGRID (9): ZFYVE28 (Affinity Capture-MS), EGF (Co-localization), Trim3 (Affinity Capture-MS), ZFYVE28 (Affinity Capture-Western), RAB5A (Co-localization), RAB4A (Co-localization), RAB7A (Co-localization), EGFR (Co-localization), ZFYVE28 (Reconstituted Complex)

ESM2 similar proteins: A0A059XKS9, A0A125YS36, A0A7J6K144, A0A7J6K7I9, A0A7J6K7Y0, A4HK17, A4I7K1, B9VXQ2, E7F4Z4, E9PSU6, P10226, P16753, P16788, P16801, P16823, P40572, Q07762, Q2PAY2, Q384Y0, Q387Y5, Q3UE17, Q40504, Q40505, Q4CTY5, Q4D7L5, Q4Q9W0, Q57XK8, Q57XV5, Q68101, Q6B9Y8, Q6DR03, Q6GV23, Q6SW46, Q6SW48, Q6SW62, Q6UDF2, Q6UDM2, Q7XLY8, Q80TL4, Q8H7N9

Diamond homologs: A0A0D1E015, A0JMD2, A1CEK1, A1DFP5, A2QWA2, A4QTV1, A8QCE4, A8XJZ8, B0G126, B0WAQ0, B3MT31, B3P851, B4G2G5, B4IC49, B4JHI7, B4K982, B4M140, B4NFJ7, B4PRU6, D2H5P6, D3ZVP7, D4A8G9, E1BLZ4, F1MM41, F7EP40, O13821, O14964, O59722, O76902, O95405, O96838, P0CS26, P0CS27, P34756, P40343, Q05B78, Q08CN9, Q0CJV3, Q0P4S0, Q0U4Z8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	174
Likely benign	18
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

4414 predictions. Top by Δscore:

Variant	Effect	Δscore
4:2271034:T:TA	donor_gain	1.0000
4:2271307:CCA:C	donor_loss	1.0000
4:2271308:CA:C	donor_loss	1.0000
4:2271310:C:A	donor_loss	1.0000
4:2271337:T:TA	donor_gain	1.0000
4:2271411:GGGT:G	acceptor_gain	1.0000
4:2271415:C:CC	acceptor_gain	1.0000
4:2271780:C:CC	acceptor_gain	1.0000
4:2273167:ACTC:A	donor_loss	1.0000
4:2273168:CTCA:C	donor_loss	1.0000
4:2273169:TCACC:T	donor_loss	1.0000
4:2273171:AC:A	donor_gain	1.0000
4:2273172:CC:C	donor_gain	1.0000
4:2273172:CCCTT:C	donor_gain	1.0000
4:2273176:T:TA	donor_gain	1.0000
4:2273182:A:C	donor_gain	1.0000
4:2274045:AGGC:A	donor_gain	1.0000
4:2335704:CCACA:C	donor_gain	1.0000
4:2335791:GGCCC:G	acceptor_loss	1.0000
4:2335793:CC:C	acceptor_gain	1.0000
4:2335793:CCCTG:C	acceptor_loss	1.0000
4:2335794:CC:C	acceptor_gain	1.0000
4:2335794:CCTG:C	acceptor_loss	1.0000
4:2335795:C:CC	acceptor_gain	1.0000
4:2335800:C:CT	acceptor_gain	1.0000
4:2335800:C:T	acceptor_gain	1.0000
4:2337403:TCA:T	donor_loss	1.0000
4:2337405:A:AC	donor_gain	1.0000
4:2337406:C:CA	donor_loss	1.0000
4:2337406:C:CC	donor_gain	1.0000

AlphaMissense

5797 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:2270773:G:C	C872W	1.000
4:2270775:A:G	C872R	1.000
4:2270782:G:C	C869W	1.000
4:2270783:C:T	C869Y	1.000
4:2270784:A:G	C869R	1.000
4:2270841:A:G	C850R	1.000
4:2270848:G:C	C847W	1.000
4:2270850:A:G	C847R	1.000
4:2271326:G:C	C839W	1.000
4:2271327:C:T	C839Y	1.000
4:2271328:A:G	C839R	1.000
4:2271331:G:C	H838D	1.000
4:2271374:G:C	C823W	1.000
4:2271376:A:G	C823R	1.000
4:2271401:C:A	W814C	1.000
4:2271401:C:G	W814C	1.000
4:2271403:A:G	W814R	1.000
4:2271403:A:T	W814R	1.000
4:2273238:A:G	L753P	1.000
4:2273250:A:G	L749P	1.000
4:2273274:A:G	L741P	1.000
4:2335714:G:T	A231D	1.000
4:2339582:A:G	L131P	1.000
4:2341487:G:C	F103L	1.000
4:2341487:G:T	F103L	1.000
4:2341489:A:G	F103L	1.000
4:2270774:C:A	C872F	0.999
4:2270774:C:G	C872S	0.999
4:2270774:C:T	C872Y	0.999
4:2270775:A:T	C872S	0.999

dbSNP variants (sampled 300 via entrez): RS1000006441 (4:2382921 A>G), RS1000011008 (4:2419669 G>A,C), RS1000011773 (4:2301358 A>C,G), RS1000057054 (4:2397931 A>G), RS1000058735 (4:2388642 T>C), RS10000777 (4:2358080 T>G), RS1000082077 (4:2333794 C>T), RS1000097573 (4:2366565 C>T), RS1000098078 (4:2393717 C>T), RS1000103600 (4:2370540 G>A), RS1000103893 (4:2405585 G>A,T), RS10001146 (4:2359054 A>G), RS1000130140 (4:2298431 C>A), RS1000140711 (4:2351590 T>G), RS1000155518 (4:2401380 G>A)

Disease associations

OMIM: gene MIM:614176 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001757_6	Schizophrenia	9.000000e-06
GCST003126_2	Influenza A (H1N1) severity	3.000000e-06
GCST003425_8	Longevity	2.000000e-06
GCST006631_39	Nicotine dependence and major depression (severity of comorbidity)	7.000000e-06
GCST007277_6	Tourette syndrome	2.000000e-06
GCST009391_512	Metabolite levels	9.000000e-06
GCST010105_119	Nicotine dependence symptom count	3.000000e-06
GCST010146_14	Serum immune biomarker levels	3.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007743	influenza A severity measurement
EFO:0007006	depressive symptom measurement
EFO:0009262	nicotine dependence symptom count
EFO:0010527	pyridoxate measurement
EFO:0004869	YKL40 measurement
EFO:0004872	inflammatory biomarker measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, affects methylation	3
Cadmium	increases abundance, decreases reaction, decreases expression	2
Smoke	decreases expression, decreases reaction	2
Cadmium Chloride	increases abundance, decreases expression	2
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
TL8-506	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
propionaldehyde	decreases expression	1
bisphenol A	decreases methylation	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Decitabine	decreases expression, decreases reaction	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Arsenic	affects methylation	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	decreases expression, affects cotreatment	1

Clinical trials (associated diseases)

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