Mammalian PIKfyve is a member of an evolutionarily ancient gene family of PtdIns(3,5)P2-synthesizing enzymes that are large proteins, represented by a single-copy gene in most, if not all, species with sequenced genomes. Mouse PIKfyve, named so after its function and domain structure (PhosphoInositide Kinase for five position containing a Fyve finger) was the first among the PtdIns(3,5)P2-synthesizing enzymes in higher eukaryotes to be identified. Three alternatively spliced forms of mouse PIKfyve, which differ by the presence or absence of exon 4 (33 nt) and/or exon 12′ (168 nt; corresponds to human exon 11) are identified thus far: PIKfyveS (2041 residues), PIKfyveL (2052 residues) and a longer form of 2108 residues.  The human PIKfyve clone has been recently assembled based on the human EST database and the generated PCR product is found to encode a protein of 2098 amino acids. PIKfyve harbors several functional domains conserved across a great evolutionary distance. 
The catalytic domain is positioned at the C-terminus of PIKfyve and displays sequence similarities with the catalytic domains in PI4Ks and PI5Ks but not with those in PI3Ks and PtdIns4Ks. This domain is responsible for the three PIKfyve activities, i.e., PtdIns(3,5)P2, PtdIns5P and phosphoprotein(s) synthesis, and mutation in the predicted ATP-binding Lys at position 1831 abolishes them all. The best characterized role of PIKfyve is within the endosomal/endocytic system, first recognized by the ability of the kinase-deficient PIKfyveK1831E mutant to induce progressively exacerbated cytoplasmic vacuolation in many cell types.The K1831E mutation, however, abrogates all three enzymatic activities of PIKfyve. Expression of dominant-negative kinase-deficient PIKfyveK1831E or depletion of PIKfyve protein in mammalian cells may delay fluid-phase transport at a post-early-endosomal step or impaired early endosome-to-TGN retrograde traffic. Molecular functions of PIKfyve are elusive but recent advances are consistent with a key role in the course of endosomal transport. PIKfyve dysfunction induces endosome enlargement and profound cytoplasmic vacuolation, likely as a result of impaired normal endosome processing and membrane exit out of endosomes.


1.Assia Shisheva. Cell Biol Int. 2008 Jun; 32(6): 591–604.