FAB1/YFR019W Summary Help

Standard Name FAB1 1
Systematic Name YFR019W
Alias SVL7 2
Feature Type ORF, Verified
Description 1-phosphatidylinositol-3-phosphate 5-kinase; vacuolar membrane kinase that generates phosphatidylinositol (3,5)P2, which is involved in vacuolar sorting and homeostasis (3 and see Summary Paragraph)
Name Description Forms Aploid and Binucleate cells 1
Chromosomal Location
ChrVI:184502 to 191338 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All FAB1 GO evidence and references
  View Computational GO annotations for FAB1
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
High-throughput
Regulators 3 genes
Resources
Pathways
Classical genetics
conditional
gain of function
misexpression
null
reduction of function
Large-scale survey
conditional
null
Resources
306 total interaction(s) for 221 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 23
  • Affinity Capture-Western: 7
  • Co-purification: 1
  • PCA: 1
  • Reconstituted Complex: 2
  • Two-hybrid: 3

Genetic Interactions
  • Dosage Lethality: 1
  • Dosage Rescue: 2
  • Negative Genetic: 160
  • Positive Genetic: 61
  • Synthetic Growth Defect: 16
  • Synthetic Lethality: 28
  • Synthetic Rescue: 1

Resources
Expression Summary
histogram
Resources
Length (a.a.) 2,278
Molecular Weight (Da) 257,419
Isoelectric Point (pI) 8.56
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrVI:184502 to 191338 | ORF Map | GBrowse
SGD ORF map
Last Update Coordinates: 2011-02-03 | Sequence: 2011-02-03
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..6837 184502..191338 2011-02-03 2011-02-03
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | E.C. | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000001915
SUMMARY PARAGRAPH for FAB1

FAB1 encodes a phosphatidylinositol(3)-phosphate 5-kinase responsible for synthesis of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) from phosphatidylinositol 3-phosphate (PtdIns(3)P; 3). Fab1p localizes to the vacuolar membrane, and is the sole kinase that synthesizes PtdIns(3,5)P2 (1, 4, 5). PtdIns(3,5)P2 is required for proper trafficking of endocytic cargo through the late endosome/multivesicular body to the vacuole lumen (6, 7, 8) and is involved in the cellular response to osmotic changes in the environment, accumulating to levels 20-fold higher than basal upon hyperosmotic stress (9).

Loss of Fab1p function leads to a variety of phenotypes, including formation of aploid and binucleate cells (hence, the name FAB1) due to improper orientation of the mitotic spindle (1). Genetic studies indicate that the large vacuole size exhibited by these mutants causes the abnormal chromosome distribution (1). Deletion mutants exhibit growth defects at 23 degrees, inviability at 37 degrees, and enlarged vacuoles at both temperatures. Further, these mutants do not properly acidify their vacuoles and lack detectable levels of PtdIns(3,5)P2 (1, 5). Overexpression of Fab1p does not increase levels of PtdIns(3,5)P2, suggesting tight regulation of this enzyme (5). Fab1p activity is activated by Vac7p, a vacuolar membrane protein that appears to have homologs only in fungi, and independently by the Vac14p-Fig4p complex, which is required for turnover of PtdIns(3,5)P2 (Fig4p is a polyphosphoinositide phosphatase; 10, 11).

S. cerevisiae contains two genes that encode phosphatidylinositol phosphate kinases (PIPkins): FAB1, and MSS4, which enodes a phosphatidylinositol-4-phosphate 5-kinase (12, 3). Fab1p orthologs have been identified in S. pombe (13), mouse (14), C. elegans (15), and humans (16), among others. Mutations in the human ortholog PIP5K3 are associated with Francois-Neetens fleck corneal dystrophy (CFD), a rare corneal disorder characterized by numerous small white flecks scattered throughout the layers of the stroma (17). Collectively, the Fab1p orthologs have 4 domains in common: the FYVE domain, which has been shown to bind the substrate Ptdins3P (18), the TCP-1/chaperonin-like domain, which appears to be required for catalytic activity, a cysteine-rich domain, the role of which is uncertain, and a PIPkin domain, which is responsible for catalytic activity (reviewed in 19).

About Phosphatidylinositol Phosphate Biosynthesis

The phosphorylated products of phosphatidylinositol (PtdIns, PI), collectively referred to as phosphoinositides or phosphatidylinositol phosphates (PtdInsPs, PIPs), are membrane-bound lipids that function as structural components of membranes, as well as regulators of many cellular processes in eukaryotes, including vesicle-mediated membrane trafficking, cell wall integrity, and actin cytoskeleton organization (reviewed in 20 and 21). PtdInsPs are also precursors of the water-soluble inositol phosphates (IPs), an important class of intracellular signaling molecules (reviewed in 22, 23 and 24).

The inositol ring of the membrane phospholipids and the water-soluble IPs are readily phosphorylated and dephosphorylated at a number of positions making them well suited as key regulators. PtdIns can be phosphorylated at one or a combination of positions (3', 4', or 5') on the inositol headgroup, generating a set of unique stereoisomers that have specific biological functions (reviewed in 20). These stereoisomers have been shown to be restricted to certain membranes (reviewed in 20). Phosphatidylinositol 4-phosphate (PtdIns4P) is the major PtdInsP species of the Golgi apparatus, where it plays a role in the vesicular trafficking of secretory proteins from the Golgi to the plasma membrane (reviewed in 20). Phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P2) is the major species found at the plasma membrane and is involved in the regulation of actin cytoskeleton organization, as well as cell wall integrity, and heat shock response pathways (reviewed in 20). Phosphatidylinositol 3-phosphate (PtdIns3P) is found predominantly at endosomal membranes and in multivesicular bodies (MVB), where it plays a role in endosomal and vacuolar membrane trafficking. Phosphatidylinositol 3,5-bisphosphate (PtdIns[3,5]P2) is found on vacuolar membranes where it plays an important role in the MVB sorting pathway (reviewed in 20).

Phosphorylation and dephosphorylation of the inositol headgroups of PtdInsPs at specific membrane locations signals the recruitment of certain proteins essential for vesicular transport (21, and reviewed in 20). PtdInsPs recruit proteins that contain PtdInsP-specific binding domains, such as the well-studied pleckstrin homology (PH) domain that recognizes the phosphorylation pattern of specific PtdInsP inositol headgroups (reviewed in 20).

A number of kinases and phosphatases are involved in the generation and interconversions of PtdInsPs, the majority of which have been well conserved during evolution (reviewed in 20). The PtdInsP kinases, in contrast to the lipid phosphatases, have a higher degree of specificity. While each kinase appears to phosphorylate only one substrate, many of the lipid phosphatases can dephosphorylate a number of substrates.

Last updated: 2007-03-02 Contact SGD

References cited on this page View Complete Literature Guide for FAB1
1) Yamamoto A, et al.  (1995) Novel PI(4)P 5-kinase homologue, Fab1p, essential for normal vacuole function and morphology in yeast. Mol Biol Cell 6(5):525-39
2) Zheng B, et al.  (1998) Isolation of yeast mutants defective for localization of vacuolar vital dyes. Proc Natl Acad Sci U S A 95(20):11721-6
3) Cooke FT, et al.  (1998) The stress-activated phosphatidylinositol 3-phosphate 5-kinase Fab1p is essential for vacuole function in S. cerevisiae. Curr Biol 8(22):1219-22
4) Dove SK, et al.  (2002) Vac14 controls PtdIns(3,5)P(2) synthesis and Fab1-dependent protein trafficking to the multivesicular body. Curr Biol 12(11):885-93
5) Gary JD, et al.  (1998) Fab1p is essential for PtdIns(3)P 5-kinase activity and the maintenance of vacuolar size and membrane homeostasis. J Cell Biol 143(1):65-79
6) Odorizzi G, et al.  (1998) Fab1p PtdIns(3)P 5-kinase function essential for protein sorting in the multivesicular body. Cell 95(6):847-58
7) Dove SK, et al.  (1997) Osmotic stress activates phosphatidylinositol-3,5-bisphosphate synthesis. Nature 390(6656):187-92
8) Shaw JD, et al.  (2003) PtdIns(3,5)P2 is required for delivery of endocytic cargo into the multivesicular body. Traffic 4(7):479-90
9) Bonangelino CJ, et al.  (2002) Osmotic stress-induced increase of phosphatidylinositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p. J Cell Biol 156(6):1015-28
10) Duex JE, et al.  (2006) The Vac14p-Fig4p complex acts independently of Vac7p and couples PI3,5P2 synthesis and turnover. J Cell Biol 172(5):693-704
11) Bonangelino CJ, et al.  (1997) Vac7p, a novel vacuolar protein, is required for normal vacuole inheritance and morphology. Mol Cell Biol 17(12):6847-58
12) Desrivieres S, et al.  (1998) MSS4, a phosphatidylinositol-4-phosphate 5-kinase required for organization of the actin cytoskeleton in Saccharomyces cerevisiae. J Biol Chem 273(25):15787-93
13) McEwen RK, et al.  (1999) Complementation analysis in PtdInsP kinase-deficient yeast mutants demonstrates that Schizosaccharomyces pombe and murine Fab1p homologues are phosphatidylinositol 3-phosphate 5-kinases. J Biol Chem 274(48):33905-12
14) Shisheva A, et al.  (1999) Cloning, characterization, and expression of a novel Zn2+-binding FYVE finger-containing phosphoinositide kinase in insulin-sensitive cells. Mol Cell Biol 19(1):623-34
15) Nicot AS, et al.  (2006) The phosphoinositide kinase PIKfyve/Fab1p regulates terminal lysosome maturation in Caenorhabditis elegans. Mol Biol Cell 17(7):3062-74
16) Nagase T, et al.  (1999) Prediction of the coding sequences of unidentified human genes. XIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res 6(1):63-70
17) Li S, et al.  (2005) Mutations in PIP5K3 are associated with Francois-Neetens mouchetee fleck corneal dystrophy. Am J Hum Genet 77(1):54-63
18) Burd CG and Emr SD  (1998) Phosphatidylinositol(3)-phosphate signaling mediated by specific binding to RING FYVE domains. Mol Cell 2(1):157-62
19) Cooke FT  (2002) Phosphatidylinositol 3,5-bisphosphate: metabolism and function. Arch Biochem Biophys 407(2):143-51
20) Strahl T and Thorner J  (2007) Synthesis and function of membrane phosphoinositides in budding yeast, Saccharomyces cerevisiae. Biochim Biophys Acta 1771(3):353-404
21) De Camilli P, et al.  (1996) Phosphoinositides as regulators in membrane traffic. Science 271(5255):1533-9
22) York JD  (2006) Regulation of nuclear processes by inositol polyphosphates. Biochim Biophys Acta 1761(5-6):552-9
23) Bennett M, et al.  (2006) Inositol pyrophosphates: metabolism and signaling. Cell Mol Life Sci 63(5):552-64
24) Bhandari R, et al.  (2007) Inositol pyrophosphate pyrotechnics. Cell Metab 5(5):321-3