FIG4 encodes a lipid phosphatase that specifically targets phosphotidylinositol 3,5-bisphosphate (PtdIns[3,5]P2) at position 5 of its inositol ring and is required for mating and responding to hyperosmotic shock (3, reviewed in 5). Fig4p contains a Sac1-like phosphatase domain in its N-terminus and is partially redundant in function with other phosphatases that have this domain (Sac1p, Inp52p, and Inp53p) (reviewed in 5). Fig4p forms a complex with Vac14p that localizes to the vacuolar membrane and this complex is involved in regulating the phosphotidylinositol 3-phosphate 5-kinase, Fab1p (3, 4 and references therein). The Fig4p-Vac14p complex also regulates both the increase and decrease in PtdIns[3,5]P2 levels after hyperosmotic shock (4, 6).

The expression of FIG4 is upregulated 40-fold in cells treated with alpha-factor (1). FIG4 is a non-essential gene. Mutations in FIG4 result in shmoo tips that are broader and less focused than those in wild type cells, abnormal actin distribution at the shmoo tip, a failure to establish mating cell polarity leading to enlarged cells with multiple bumps at their periphery, and overall reduced mating efficiency (1). All of the Sac1-like domain containing proteins are highly conserved from yeast to human; mammalian members of this protein family include synaptojanin-1 (SYNJ1) and synaptojanin -2 (SYNJ2) (reviewed in 5).

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 5 and 7). PtdInsPs are also precursors of the water-soluble inositol phosphates (IPs), an important class of intracellular signaling molecules (reviewed in 8, 9 and 10).

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 5). These stereoisomers have been shown to be restricted to certain membranes (reviewed in 5). 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 5). 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 5). 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 5).

Phosphorylation and dephosphorylation of the inositol headgroups of PtdInsPs at specific membrane locations signals the recruitment of certain proteins essential for vesicular transport (7, and reviewed in 5). 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 5).

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 5). 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: 2008-05-08