Slm1 and Slm2 Are Novel Substrates of the Calcineurin Phosphatase Required for Heat Stress-Induced Endocytosis of the Yeast Uracil Permease

Bultynck, Geert; Heath, Victoria L.; Majeed, Alia P.; Galan, Jean-Marc; Haguenauer‐Tsapis, Rosine; Cyert, Martha S.

doi:10.1128/mcb.01973-05

Cited by 102 publications

(129 citation statements)

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“…This observation suggests that MSS4 and TORC2 may regulate some aspect of sphingolipid synthesis, and perhaps consequently endocytosis. This hypothesis has indeed found recent support: SLM function is required for proper sphingolipid metabolism and heat stress-induced endocytosis of the uracil permease (Bultynck et al, 2006;Tabuchi et al, 2006). Calcineurin is also involved in these processes but mechanistic details remain to be established.…”

Section: Endocytosismentioning

confidence: 86%

“…Building on this, the Cyert and Emr groups (Bultynck et al, 2006;Tabuchi et al, 2006) have confirmed that the SLMs interact with, and are dephosphorylated by, calcineurin. Loss of SLM function results in increased expression of CRZ1 targets (CRZ1 is a transcription factor negatively regulated by calcineurin) and genetic or chemical inhibition of calcineurin activity suppresses the lethality and actin depolarization of slm mutants (Tabuchi et al, 2006).…”

Section: Calcineurinmentioning

confidence: 94%

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Cell growth control: little eukaryotes make big contributions

2006

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The story of rapamycin is a pharmaceutical fairytale. Discovered as an antifungal activity in a soil sample collected on Easter Island, this macrocyclic lactone and its derivatives are now billion dollar drugs, used in, and being evaluated for, a number of clinical applications. Taking advantage of its antifungal property, the molecular Target Of Rapamycin, TOR, was first described in the budding yeast Saccharomyces cerevisiae. TORs encode large, Ser/Thr protein kinases that reside in two distinct, structurally and functionally conserved, multi-protein complexes. In yeast, these complexes coordinate many different aspects of cell growth. TOR complex 1, TORC1, promotes protein synthesis and other anabolic processes, while inhibiting macroautophagy and other catabolic and stress-response processes. TORC2 primarily regulates cell polarity, although additional readouts of this complex are beginning to be characterized. TORC1 appears to be activated by nutrient cues and inhibited by stresses and rapamycin; however, detailed mechanisms are not known. In contrast, TORC2 is insensitive to rapamycin and physiological regulators of this complex have yet to be defined. Given the unsurpassed resources available to yeast researchers, this simple eukaryote continues to contribute to our understanding of eukaryotic cell growth in general and TOR function in particular

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Section: Endocytosismentioning

confidence: 86%

Section: Calcineurinmentioning

confidence: 94%

Cell growth control: little eukaryotes make big contributions

2006

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“…The calcineurin phosphatase also mediates Slm1 dephosphorylation and counteracts TORC2 signaling (Bultynck et al 2006;Mulet Figure 7 In vitro phosphorylation of Slm1 by immunopurified HA-Tor2. (A) Wild-type (SW70) and isogenic sac7D (TPY1246) and far11D (TPY1249) cells expressing N-terminal 3·HA-tagged Tor2 from the TOR2 genomic locus were grown in YPD medium.…”

Section: Discussionmentioning

confidence: 99%

TORC2 Signaling Is Antagonized by Protein Phosphatase 2A and the Far Complex in Saccharomyces cerevisiae

Pracheil

Thornton²,

Liu

2012

Genetics

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The target of rapamycin (TOR) kinase, a central regulator of eukaryotic cell growth, exists in two essential, yet distinct, TOR kinase complexes in the budding yeast Saccharomyces cerevisiae: rapamycin-sensitive TORC1 and rapamycin-insensitive TORC2. Lst8, a component of both TOR complexes, is essential for cell viability. However, it is unclear whether the essential function of Lst8 is linked to TORC1, TORC2, or both. To that end, we carried out a genetic screen to isolate lst8 deletion suppressor mutants. Here we report that mutations in SAC7 and FAR11 suppress lethality of lst8D and TORC2-deficient (tor2-21) mutations but not TORC1 inactivation, suggesting that the essential function of Lst8 is linked only to TORC2. More importantly, characterization of lst8D bypass mutants reveals a role for protein phosphatase 2A (PP2A) in the regulation of TORC2 signaling. We show that Far11, a member of the Far3-7-8-9-10-11 complex involved in pheromone-induced cell cycle arrest, interacts with Tpd3 and Pph21, conserved components of PP2A, and deletions of components of the Far3-7-8-9-10-11 complex and PP2A rescue growth defects in lst8D and tor2-21 mutants. In addition, loss of the regulatory B9 subunit of PP2A Rts1 or Far11 restores phosphorylation to the TORC2 substrate Slm1 in a tor2-21 mutant. Mammalian Far11 orthologs FAM40A/B exist in a complex with PP2A known as STRIPAK, suggesting a conserved functional association of PP2A and Far11. Antagonism of TORC2 signaling by PP2A-Far11 represents a novel regulatory mechanism for controlling spatial cell growth of yeast.T HE target of rapamycin (TOR) kinase is a phosphatidylinositol kinase-related protein kinase that controls eukaryotic cell growth and proliferation in response to nutrient conditions (Inoki et al. 2005;Wullschleger et al. 2006;Zoncu et al. 2011). The TOR kinase is inhibited by the complex of rapamycin and Fpr1, a peptidyl-prolyl cis-trans isomerase. The TOR kinase is conserved in eukaryotes. Unlike fungal species, which may possess two TOR kinases, higher eukaryotes such as humans possess only one. The TOR kinase exists in multi-protein complexes, which have been purified from many different eukaryotic systems. There exist two distinct TOR kinase complexes. In yeast, rapamycin-sensitive TORC1 consists of Tor1 or Tor2, Lst8, Kog1, and Tco89, and rapamycin-insensitive TORC2 consists of Tor2, Lst8, Avo1, Avo2, Avo3, and Bit61 (Loewith et al. 2002;Wedaman et al. 2003;Reinke et al. 2004). Both complexes are partially conserved in mammals: mTORC1 contains the yeast Kog1 ortholog raptor, while mTORC2 contains mSin1 and rictor, orthologs of yeast Avo1 and Avo3, respectively; GbL, the ortholog of yeast Lst8, exists in both mTORC1 and mTORC2 (Zoncu et al. 2011).TOR regulates cell growth by sensing and responding to changes in nutrient conditions (Schmelzle and Hall 2000). TORC1 has an essential function involving the regulation of cell growth that is carried out when either Tor1 or Tor2 is in the complex. Under favorable growth conditions, TORC1 promotes ce...

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“…7,11,15,17,18,19 Precise placement of the PxIxIT segment relative to the site of dephosphorylation may not be necessary as long as there is sufficient flexibility to position the targeted phosphorylated residues in the catalytic site of calcineurin. The role of a flexible spacer has been examined in the case of the phospho-CDK2/cyclin A interaction with its substrates.…”

Section: Connecting Specific Substrate Recognition To Dephosphorylationmentioning

confidence: 99%

“…7 These results suggest that the strength of calcineurin-NFAT binding, or a related variable, such as the dissociation rate of the complex, is tuned in a narrow window. Several yeast calcineurin substrates (Crz1, Slm1, Slm2, and Hph1) utilize the PxIxIT docking site, [17][18][19] and normal signalling in the calcineurinCrz1 pathway depends on the precise affinity of the interaction. 20 The lessons emerging from observations on mammalian and yeast substrates are that…”

Section: Introductionmentioning

confidence: 99%