). Ymr1p partially overlaps in function with other lipid phosphatases, in particular Inp53p (2). Due to this partial redundancy, ymr1 null mutants are viable and do not display any obvious phenotype beyond elevated levels of PtdIns3P (1). ymr1 inp53 double null mutants, however, have fragmented vacuoles and show defects in cytoplasm to vacuole transport (Cvt pathway), endosome to vacuole transport, sorting via multivesicular bodies, and localization of retromer complex members. ymr1 inp52 inp53 triple null mutants are inviable (2).
Ymr1p is homologous to phosphatases in the myotubularin family. The founding member of this group is the human gene MTM1, mutations in which cause the severe congenitive muscle disorder X-linked recessive myotubular myopathy (1, 3 and references therein).
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 4 and 5). PtdInsPs are also precursors of the water-soluble inositol phosphates (IPs), an important class of intracellular signaling molecules (reviewed in 6, 7 and 8).
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 4). These stereoisomers have been shown to be restricted to certain membranes (reviewed in 4). 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 4). 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 4). 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 4).
Phosphorylation and dephosphorylation of the inositol headgroups of PtdInsPs at specific membrane locations signals the recruitment of certain proteins essential for vesicular transport (5, and reviewed in 4). 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 4).
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 4). 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