PIKFYVE

Fig1. General scheme of endocytosis and proposed model for the locus and mode of action of PIKfyve and its physically associated partners. (Assia Shisheva, 2008)

What is PIKFYVE protein?

PIKFYVE (phosphoinositide kinase, FYVE-type zinc finger containing) gene is a protein coding gene which situated on the long arm of chromosome 2 at locus 2q34. PIKFYVE protein is a phosphatidylinositol 3-phosphate 5-kinase, the full name of which is Phosphatidylinositol 3-phosphate 5-kinase. It plays a key role in a variety of intracellular functions, including regulating endometrial homeostasis, controlling endometrial transport, transcriptional regulation, and participating in cell response to external stimuli. PIKFYVE proteins phosphorylate PI(3)P (phosphatidylinositol 3-phosphate) to PI(3,5)P2 (phosphatidylinositol 3, 5-diphosphate), an important class of phosphatidylinositol signaling molecules involved in the regulation of a variety of cellular processes. PIKFYVE protein is consisted of 2098 amino acids and its molecular mass is approximately 237.1 kDa.

What is the function of PIKFYVE protein?

PIKFYVE protein generates PI(3,5)P2 by phosphorylation of phosphatidylinositol 3-phosphate (PI(3)P), which is an important intracellular signaling molecule. PIKFYVE proteins play a key role in the function of the endoplasmic reticulum and lysosomes, influencing their morphology, size and dynamics. PIKFYVE proteins are involved in regulating endosome transport, retrograde transport from endosome to Golgi apparatus, and endosome to cell surface cycling. In addition to being a lipid kinase, PIKFYVE also has protein kinase activity, regulating its lipid kinase activity negatively through autophosphorylation. The PIKFYVE protein is involved in regulating the transcription of specific genes and affects the physiological function of cells.

PIKFYVE Related Signaling Pathway

In the phosphatidylinositol signaling pathway, PIKFYVE generates PI(3,5)P2 by phosphorylating phosphatidylinositol 3-phosphate (PI(3)P), a process that plays a key role in regulating endometrial homeostasis, endosomal transport and autophagy. PIKFYVE is a regulator of TFEB, a master regulator of autophagy and lysosomal biogenesis. PIKFYVE inhibits the nuclear localization of induced TFEB. PIKFYVE affects the PI3K/Akt/mTOR signaling pathway through its lipid kinase activity, which plays a role in cell growth, metabolism, and survival. PIKFYVE is involved in the entry of viruses such as Ebola virus, Marburg virus and SARS-CoV-2 into host cells, and pharmacological inhibition of PIKFYVE can inhibit viral replication.

PIKFYVE Related Diseases

PIKFYVE has been linked to the development of cancer, for example in B-cell non-Hodgkin lymphoma cell lines where the PIKFYVE inhibitor apilimod has shown anti-proliferative effects. PIKFYVE is involved in the entry of viruses such as Ebola virus, Marburg virus and SARS-CoV-2 into host cells, and pharmacological inhibition of PIKFYVE can inhibit viral replication. PIKFYVE also has a role in neurodegenerative diseases, such as the PIKFYVE inhibitor YM201636, which was found to improve motor neuron survival in patients with amyotrophic lateral sclerosis (ALS) caused by repeated expansion of the C9ORF72 gene. PIKFYVE is a regulator of the subcellular distribution of tau aggregates, and its pharmacological inhibition reduces lysosomal delivery of tau aggregates, preventing a key step in tau disease.

Bioapplications of PIKFYVE

PIKFYVE is a therapeutic target, and its inhibitors are being investigated for the treatment of a variety of diseases, including neurodegenerative diseases, cancer, and viral infections. PIKFYVE inhibitors such as apilimod and YM201636 are in clinical trials to treat neurodegenerative diseases such as ALS, as well as viral infections such as COVID-19. PIKFYVE and its associated signaling molecules may serve as biomarkers for disease diagnosis and therapeutic monitoring.

Case Study 1: Yuanyuan Qiao, 2021

Multi-tyrosine kinase inhibitors (MTKIs) have thus far had limited success in the treatment of castration-resistant prostate cancer (CRPC). Here, the researchers report a phase I-cleared orally bioavailable MTKI, ESK981, with a novel autophagy inhibitory property that decreased tumor growth in diverse preclinical models of CRPC. The anti-tumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated CXCL10 expression through the interferon gamma pathway and promoted functional T cell infiltration, which resulted in enhanced therapeutic response to immune checkpoint blockade. Mechanistically, they identify the lipid kinase PIKfyve as the direct target of ESK981. PIKfyve-knockdown recapitulated ESK981's anti-tumor activity and enhanced the therapeutic benefit of immune checkpoint blockade.

Fig1. Representative dissociation constant (Kd) curve of ESK981 against lipid kinases PIKfyve, PIP5K1C, PIP5K1A, and PIK3CA.

Fig2. Average tumor volume of shPikfyve Myc-CaP with or without doxycycline chow in NSG mice.

Case Study 2: Cansu Karabiyik, 2021

Autophagy is an essential catabolic process induced to provide cellular energy sources in response to nutrient limitation through the activation of kinases, like AMP-activated protein kinase (AMPK) and ULK1. Although glucose starvation induces autophagy, the exact mechanism underlying this signaling has yet to be elucidated. Here, the researchers reveal a role for ULK1 in non-canonical autophagy signaling using diverse cell lines. ULK1 activated by AMPK during glucose starvation phosphorylates the lipid kinase PIKfyve on S1548, thereby increasing its activity and the synthesis of the phospholipid PI(5)P without changing the levels of PI(3,5)P2. ULK1-mediated activation of PIKfyve enhances the formation of PI(5)P-containing autophagosomes upon glucose starvation, resulting in an increase in autophagy flux. Phospho-mimic PIKfyve S1548D drives autophagy upregulation and lowers autophagy substrate levels.

Fig3. Endogenous PIKfyve immunoprecipitated from HEK 293T cells.

Fig4. HeLa cells transfected with FLAG-LKB1, GFP-PHD3x, FLAG-ATG4B mutant ± HA-PIKfyve S1548D.

PIKFYVE has several biochemical functions, for example, 1-phosphatidylinositol-3-phosphate 5-kinase activity,1-phosphatidylinositol-4-phosphate 5-kinase activity,ATP binding. Some of the functions are cooperated with other proteins, some of the functions could acted by PIKFYVE itself. We selected most functions PIKFYVE had, and list some proteins which have the same functions with PIKFYVE. You can find most of the proteins on our site.

PIKFYVE has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with PIKFYVE here. Most of them are supplied by our site. Hope this information will be useful for your research of PIKFYVE.

VAC14;Dlg4;1C