SUMMARY PARAGRAPH for TFS1
TFS1 encodes an anionic phospholipid binding protein with roles in regulation of the protein kinase A (PKA) signaling pathway as well as inhibition of the vacuolar protease CPY (carboxypeptidase Y, encoded by Prc1p; 6, 5). TFS1 was first identified as an allele-specific, high copy suppressor of the cdc25-1 mutation (10, 1). Suppression was found to be mediated through interaction with and inhibition of the GTPase-activating protein Ira2p, a negative regulator of RAS function (4). Loss of the negative regulation of RAS protein allows the cAMP/PKA pathway to be activated, which in turn controls cell growth and metabolism. Tfs1p was independently isolated as a 25 kDa inhibitor of vacuolar carboxypeptidase Y (3). The protein was purified and shown to undergo N-terminal acetylation that is mediated by NatB (Nat3p and Mdm20p) and is required for its role in CPY inhibition (3, 5). Purified Tfs1p is a monomer that has multiple binding sites for CPY (11, 12). CPY binding prevents interaction of Tfs1p with phospholipid membranes (6). In vitro assays indicate that Tfs1p has affinity for anionic phospholipids, particularly phosphatidylserine, PtdIns(3)P, PtdIns(3,4)P2, and PtdIns(3,4,5)P3 (6). During log phase growth, Tfs1p is found in the cytoplasm; it is relocalized to the vacuole in stationary phase (6, 13).
TFS1 is highly transcribed in stationary phase (13). Transcription is also modulated by environmental stress; the TFS1 promoter contains two stress-responsive (STRE) elements, and TFS1 expression is elevated in response to oxidative stress, diauxic shift, or heat shock (14, 15, 16). Null mutations in TFS1 confer increased resistance to heat shock, as well as increased CPY activity (due to loss of inhibition mediated by Tfs1p); overexpression confers decreased resistance to heat shock (4, 5). In addition, null mutations suppress sensitivity to caffeine, which inhibits growth by increasing cAMP concentration and consequently PKA activity (5).
TFS1 is a member of a family of proteins termed PEBP (phosphatidylethanolamine-binding protein), which includes mammalian PEBP1, a protein that is found in reproductive and brain tissue, and Arabidopsis floral regulators FL and TFL1 (17; reviewed in 18). PEBPs appear to play roles in different protein inhibition activities (reviewed in 5). Notably, PEBP1 is involved in suppressing metastasis in prostate cancer (19). Members of this family contain a central beta-sheet structure and a small surface anion-binding cavity (reviewed in 6). Mutant analysis indicates that both this cavity and the N-terminal region of Tfs1p are necessary for interaction of Tfs1p and Ira2p (4, 20).
Last updated: 2009-08-24