PIKFYVE

Official Full Name

phosphoinositide kinase, FYVE-type zinc finger containing

Organism

Homo sapiens

GeneID

200576

Background

Phosphorylated derivatives of phosphatidylinositol (PtdIns) regulate cytoskeletal functions, membrane trafficking, and receptor signaling by recruiting protein complexes to cell- and endosomal-membranes. Humans have multiple PtdIns proteins that differ by the degree and position of phosphorylation of the inositol ring. This gene encodes an enzyme (PIKfyve; also known as phosphatidylinositol-3-phosphate 5-kinase type III or PIPKIII) that phosphorylates the D-5 position in PtdIns and phosphatidylinositol-3-phosphate (PtdIns3P) to make PtdIns5P and PtdIns(3,5)biphosphate. The D-5 position also can be phosphorylated by type I PtdIns4P-5-kinases (PIP5Ks) that are encoded by distinct genes and preferentially phosphorylate D-4 phosphorylated PtdIns. In contrast, PIKfyve preferentially phosphorylates D-3 phosphorylated PtdIns. In addition to being a lipid kinase, PIKfyve also has protein kinase activity. PIKfyve regulates endomembrane homeostasis and plays a role in the biogenesis of endosome carrier vesicles from early endosomes. The protein plays a key role in cell entry of ebola virus and SARS-CoV-2 by endocytosis Mutations in this gene cause corneal fleck dystrophy (CFD); an autosomal dominant disorder characterized by numerous small white flecks present in all layers of the corneal stroma. Histologically, these flecks appear to be keratocytes distended with lipid and mucopolysaccharide filled intracytoplasmic vacuoles. [provided by RefSeq, Jul 2021]

Synonyms

CFD; FAB1; HEL37; PIP5K; PIP5K3; ZFYVE29;

Protein Sequence

MATDDKTSPTLDSANDLPRSPTSPSHLTHFKPLTPDQDEPPFKSAYSSFVNLFRFNKERAEGGQGEQQPLSGSWTSPQLPSRTQSVRSPTPYKKQLNEELQRRSSALDTRRKAEPTFGGHDPRTAVQLRSLSTVLKRLKEIMEGKSQDSDLKQYWMPDSQCKECYDCSEKFTTFRRRHHCRLCGQIFCSRCCNQEIPGKFMGYTGDLRACTYCRKIALSYAHSTDSNSIGEDLNALSDSACSVSVLDPSEPRTPVGSRKASRNIFLEDDLAWQSLIHPDSSNTPLSTRLVSVQEDAGKSPARNRSASITNLSLDRSGSPMVPSYETSVSPQANRTYVRTETTEDERKILLDSVQLKDLWKKICHHSSGMEFQDHRYWLRTHPNCIVGKELVNWLIRNGHIATRAQAIAIGQAMVDGRWLDCVSHHDQLFRDEYALYRPLQSTEFSETPSPDSDSVNSVEGHSEPSWFKDIKFDDSDTEQIAEEGDDNLANSASPSKRTSVSSFQSTVDSDSAASISLNVELDNVNFHIKKPSKYPHVPPHPADQKEYLISDTGGQQLSISDAFIKESLFNRRVEEKSKELPFTPLGWHHNNLELLREENGEKQAMERLLSANHNHMMALLQQLLHSDSLSSSWRDIIVSLVCQVVQTVRPDVKNQDDDMDIRQFVHIKKIPGGKKFDSVVVNGFVCTKNIAHKKMSSCIKNPKILLLKCSIEYLYREETKFTCIDPIVLQEREFLKNYVQRIVDVRPTLVLVEKTVSRIAQDMLLEHGITLVINVKSQVLERISRMTQGDLVMSMDQLLTKPHLGTCHKFYMQIFQLPNEQTKTLMFFEGCPQHLGCTIKLRGGSDYELARVKEILIFMICVAYHSQLEISFLMDEFAMPPTLMQNPSFHSLIEGRGHEGAVQEQYGGGSIPWDPDIPPESLPCDDSSLLELRIVFEKGEQENKNLPQAVASVKHQEHSTTACPAGLPCAFFAPVPESLLPLPVDDQQDALGSEQPETLQQTVVLQDPKSQIRAFRDPLQDDTGLYVTEEVTSSEDKRKTYSLAFKQELKDVILCISPVITFREPFLLTEKGMRCSTRDYFAEQVYWSPLLNKEFKEMENRRKKQLLRDLSGLQGMNGSIQAKSIQVLPSHELVSTRIAEHLGDSQSLGRMLADYRARGGRIQPKNSDPFAHSKDASSTSSGQSGSKNEGDEERGLILSDAVWSTKVDCLNPINHQRLCVLFSSSSAQSSNAPSACVSPWIVTMEFYGKNDLTLGIFLERYCFRPSYQCPSMFCDTPMVHHIRRFVHGQGCVQIILKELDSPVPGYQHTILTYSWCRICKQVTPVVALSNESWSMSFAKYLELRFYGHQYTRRANAEPCGHSIHHDYHQYFSYNQMVASFSYSPIRLLEVCVPLPKIFIKRQAPLKVSLLQDLKDFFQKVSQVYVAIDERLASLKTDTFSKTREEKMEDIFAQKEMEEGEFKNWIEKMQARLMSSSVDTPQQLQSVFESLIAKKQSLCEVLQAWNNRLQDLFQQEKGRKRPSVPPSPGRLRQGEESKISAMDASPRNISPGLQNGEKEDRFLTTLSSQSSTSSTHLQLPTPPEVMSEQSVGGPPELDTASSSEDVFDGHLLGSTDSQVKEKSTMKAIFANLLPGNSYNPIPFPFDPDKHYLMYEHERVPIAVCEKEPSSIIAFALSCKEYRNALEELSKATQWNSAEEGLPTNSTSDSRPKSSSPIRLPEMSGGQTNRTTETEPQPTKKASGMLSFFRGTAGKSPDLSSQKRETLRGADSAYYQVGQTGKEGTENQGVEPQDEVDGGDTQKKQLINPHVELQFSDANAKFYCRLYYAGEFHKMREVILDSSEEDFIRSLSHSSPWQARGGKSGAAFYATEDDRFILKQMPRLEVQSFLDFAPHYFNYITNAVQQKRPTALAKILGVYRIGYKNSQNNTEKKLDLLVMENLFYGRKMAQVFDLKGSLRNRNVKTDTGKESCDVVLLDENLLKMVRDNPLYIRSHSKAVLRTSIHSDSHFLSSHLIIDYSLLVGRDDTSNELVVGIIDYIRTFTWDKKLEMVVKSTGILGGQGKMPTVVSPELYRTRFCEAMDKYFLMVPDHWTGLGLNC

Open

Disease

Malignant haematopoietic neoplasm, Mature B-cell leukaemia

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Detailed Information

The PIKFYVE (Phosphoinositide Kinase, FYVE-Type Zinc Finger Containing) gene is located on human chromosome 2q34 and encodes a bifunctional enzyme with both lipid kinase and protein kinase activities. Belonging to the FYVE-type zinc finger family, PIKFYVE specifically catalyzes phosphorylation of phosphatidylinositol 3-phosphate (PtdIns3P) and phosphatidylinositol (PtdIns) at the 5-position, generating phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P₂) and phosphatidylinositol 5-phosphate (PtdIns5P), respectively. Structurally, the protein comprises an N-terminal CHK domain, a central phosphoinositide kinase catalytic domain, and a C-terminal FYVE zinc finger domain, the latter mediating precise localization to the endosome–lysosome system via PtdIns3P binding. Unlike class I phosphoinositide kinases, PIKFYVE exhibits higher affinity for D-3 phosphorylated substrates, positioning it as a central regulator of lysosomal membrane lipid homeostasis. Mutations in PIKFYVE can lead to autosomal dominant corneal fleck dystrophy, characterized by vesiculated keratocytes laden with lipids and glycosaminoglycans, highlighting its essential role in lipid metabolism.

Figure 1. Domain architecture of PIKfyve showing its predicted kinase and CCR/CCT domains and the cryo-EM structure of the PIKfyve–VAC14–FIG4 complex. (Burke JE, et al., 2022)

Biological Functions and Pathological Mechanisms

PIKFYVE maintains dynamic homeostasis of the endosome–lysosome system through regulation of PtdIns(3,5)P₂ synthesis and turnover. Its functions encompass membrane trafficking and autophagy regulation, lipid metabolism reprogramming, and immune or infection modulation. The PIKFYVE complex, which includes FIG4 and VAC14, drives early-to-late endosome conversion and mediates endosomal vesicle budding, affecting nuclear translocation of receptors such as EGFR and antigen presentation. Inhibition of PIKFYVE disrupts autophagic flux, causing lysosomal vacuolization and accumulation of autophagic substrates, ultimately triggering cellular metabolic stress. In pancreatic ductal adenocarcinoma, elevated PIKFYVE expression supports tumor cell survival under nutrient-deprived conditions. PIKFYVE inhibition results in abnormal lysosomal cholesterol accumulation, activation of sterol regulatory element-binding proteins (SREBP1), upregulation of fatty acid synthase and sphingolipid biosynthesis genes, and a shift toward de novo lipogenesis. PIKFYVE also regulates neutrophil chemotaxis and reactive oxygen species generation and modulates macrophage lysosomal degradation capacity. It serves as a critical host factor for viral endocytosis, including SARS-CoV-2, with inhibition blocking viral entry.

Clinical Associations and Translational Research

Aberrant PIKFYVE activation has been linked to various malignancies. In hepatocellular carcinoma, PIKFYVE expression is elevated compared with adjacent non-tumor tissues, correlating negatively with tumor differentiation and serving as an independent prognostic factor. In pancreatic cancer, PIKFYVE is selectively overexpressed in tumor tissues, whereas normal pancreatic tissue tolerates its absence. Conditional Pikfyve knockout in KPC mouse models significantly suppresses tumor growth and prolongs survival.

Targeted Therapeutic Strategies

PIKFYVE-directed therapies include small-molecule inhibitors and combination approaches. Apilimod, an oral PIKFYVE inhibitor, alleviates cisplatin-induced acute kidney injury by promoting TFEB nuclear translocation and activating PGC1α-mediated fatty acid oxidation, reducing lipotoxicity and inflammation without compromising cisplatin antitumor activity. Another inhibitor, ESK981, achieves over 50% tumor growth inhibition as a single agent in pancreatic xenograft models. Combination strategies leverage synthetic lethality: PIKFYVE inhibition triggers KRAS-MAPK–driven compensatory lipid synthesis, which can be counteracted with KRAS inhibitors (e.g., MRTX1133) or MEK inhibitors (e.g., Trametinib). Preclinical studies show that ESK981 plus Trametinib extends survival over fivefold in PDAC mouse models, nearly eradicating tumors. ESK981 has advanced to Phase II clinical trials, representing a novel paradigm for pancreatic cancer therapy.

Challenges and Future Directions

Despite promising therapeutic potential, PIKFYVE-targeted interventions face several challenges. Tumor cells may evade inhibition via metabolic bypass pathways, including acetyl-CoA carboxylase or sterol-O-acyltransferase. Long-term inhibition may impact lysosomal function in cardiomyocytes, necessitating tissue-targeted delivery systems. Kinase domain mutations, such as D2508Y, can confer drug resistance by impeding inhibitor binding. Future research aims to develop allosteric inhibitors targeting the FYVE zinc finger domain, PROTAC-based degraders, and patient stratification strategies informed by lysosomal lipidomics. As KRAS/MAPK pathway inhibitors become more clinically prevalent, PIKFYVE combination therapies hold promise to reshape solid tumor treatment.

Reference

Rivero-Ríos P, Weisman LS. Roles of PIKfyve in multiple cellular pathways. Curr Opin Cell Biol. 2022 Jun;76:102086.
Ikonomov OC, Sbrissa D, Shisheva A. Small molecule PIKfyve inhibitors as cancer therapeutics: Translational promises and limitations. Toxicol Appl Pharmacol. 2019 Nov 15;383:114771.
Burke JE, Triscott J, Emerling BM, et al. Beyond PI3Ks: targeting phosphoinositide kinases in disease. Nat Rev Drug Discov. 2023 May;22(5):357-386.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry