Disease relevance of SLT2

• A novel connection between the yeast Cdc42 GTPase and the Slt2-mediated cell integrity pathway identified through the effect of secreted Salmonella GTPase modulators [1].
• C. neoformans mutants lacking Mpk1 are attenuated for virulence in the mouse model of cryptococcosis [2].
• The ROS hypersensitivity of an slt2 mutant correlates with elevated programmed cell death as determined by TUNEL assays [3].

High impact information on SLT2

• Sir3p phosphorylation by the Slt2p pathway effects redistribution of silencing function and shortened lifespan [4].
• Thus, Slt2p is an enzymatic regulator of silencing function that couples commitment to cell growth and shorter lifespan [4].
• Role of calcineurin and Mpk1 in regulating the onset of mitosis in budding yeast [5].
• Calcineurin and Mpk1 regulate Swel activation at the transcriptional and posttranslational levels, respectively, and both are required for the calcium-induced delay in G2 phase [5].
• We show that the PKC1-regulated pathway is important for induced thermotolerance and that the MPK1 protein kinase (the MAPK of this pathway) is strongly activated by mild heat shock [6].

Biological context of SLT2

• The SLT2 (MPK1) MAP kinase homolog is involved in polarized cell growth in Saccharomyces cerevisiae [7].
• We show that slt2 mutants exhibit phenotypes similar to those shown by mutants of the yeast actin cytoskeleton, including delocalization of chitin deposition and of actin cortical spots and the accumulation of secretory pathway membranes and vesicles [7].
• The protein kinase C of Saccharomyces cerevisiae, Pkc1, regulates a MAP kinase, Mpk1, whose activity is stimulated at the G1-S transition of the cell cycle and by perturbations to the cell surface, e.g. induced by heat shock [8].
• The MPK1 gene possesses a 1.5-kb uninterrupted open reading frame predicted to encode a 53-kDa protein [9].
• To search for genes that interact with the Mpk1 pathway, we isolated both chromosomal mutations and dosage suppressor genes that ameliorate the growth-inhibitory effect of overexpressed Mkk1P386 [10].

Anatomical context of SLT2

• Cell cycle commitment is associated not only with major alterations in gene expression but also with highly polarized cell growth; the mitogen-activated protein kinase (MAPK) Slt2 is required to maintain cell wall integrity during periods of polarized growth and cell wall stress [11].
• We characterized the defect that underlies this genetic interaction and found that sac1 Delta slt2 Delta cells arrest as large-budded cells because they fail to separate at the end of mitosis [12].
• In yeast, the Mpk1p-MAP kinase pathway functions to maintain the integrity of the cytoskeleton and the cell wall [13].
• Both Slt2 phosphorylation and FKS2-lacZ induction could be largely prevented by providing osmotic support to the plasma membrane [14].

Associations of SLT2 with chemical compounds

• Deletion of the MPK1/SLT2 gene disturbs the glucose-triggered K(m) decrease in ATPase [15].
• Mutation of the presumptive phosphorylated tyrosine and threonine residues of Mpk1p individually to phenylalanine and alanine, respectively, severely impaired Mpk1p function [9].
• In contrast, the Slt2p C-terminal domain (162 residues) that carries a glutamine-rich fragment followed by a 16 polyglutamine tract, was shown to be dispensable for complementation and in vivo association with Mkk1p and Mkk2p [16].
• Overexpression of SIW14 also rescued the caffeine sensitivity of the slt2 mutant isolated in the screen, but this was not due to alteration of the phosphorylation state of Slt2 [17].
• A role for MID2 in the cell integrity pathway is further supported by the finding that MID2 is required for induction of Mpk1p tyrosine phosphorylation during exposure to alpha-factor, calcofluor white, or high temperature [18].

Physical interactions of SLT2

• In this paper, we demonstrate by two-hybrid, in vitro immunoprecipitation and tandem affinity purification (TAP) methods that Knr4p physically interacts with Slt2p [19].
• Consistent with a role of this phosphatase on cell wall physiology, cells lacking Msg5 displayed an increased sensitivity to the cell wall-interfering compound Congo Red. We have observed that the N-terminal non-catalytic region of this phosphatase was responsible for binding to the kinase domain of Slt2, the MAPK that operates in this pathway [20].

Enzymatic interactions of SLT2

• Ptp2 was more efficient than Ptp3 at binding and dephosphorylating Mpk1 [21].
• Reciprocally, Slt2 phosphorylated Msg5 as a consequence of the activation of the cell integrity pathway [20].
• The Mpk1 MAP kinase of the Saccharomyces cerevisiae cell wall integrity signalling pathway phosphorylates and activates the Rlm1 transcription factor in response to cell wall stress [22].

Regulatory relationships of SLT2

• The defect in recovery of the delta cnb1 mutant was suppressed by overexpression of MPK1 [23].
• Furthermore, overexpression of the Pkc1-controlled mitogen-activated protein (MAP) kinase Mpk1 suppressed the actin defect of tor2ts and rho1-2ts mutants [24].
• Cdc42-induced activation of Slt2 occurs in a mating and filamentation pathway-dependent manner, but it does not require the function of Rho1, which is the GTPase that operates in the cell integrity pathway [1].
• Moreover, the expression of genes previously identified as targets of the Mpk1 pathway are also up-regulated in strains lacking PPZ1 and -2 [25].
• Calcineurin and Mpk1 activate Swe1 at the transcriptional and post-translational level, respectively, and both pathways are essential for the cell cycle delay [26].

Other interactions of SLT2

• We suggest that Slt2p functions downstream or in parallel with Cdc28p in promoting bud formation and apical growth [7].
• Our results suggest that Rlm1 functions as a transcription factor downstream of Mpk1 that is subject to activation by the Mpk1 mitogen-activated protein kinase pathway [10].
• The MPK1 gene was isolated as a dosage-dependent suppressor of the cell lysis defect associated with deletion of the BCK1 gene [9].
• Transcriptional coregulation by the cell integrity mitogen-activated protein kinase Slt2 and the cell cycle regulator Swi4 [11].
• Expression of Xenopus MAP kinase suppressed the defect associated with loss of MPK1 but not the mating-related defects associated with loss of FUS3 or KSS1, indicating functional conservation between the former two protein kinases [9].

Analytical, diagnostic and therapeutic context of SLT2

• We performed DNA microarray analysis and identified other genes whose expression was reduced in both SLT2 and SWI4 deletion strains [11].
• The SLT2 allele of several lyt2 strains was both rescued and amplified by PCR [27].
• Further genetic analysis combined with immunoblotting revealed that Kss1, one of the mating mitogen-activated protein kinases (MAPKs), and Mpk1, an MAPK of the cell integrity pathway, participated in l-dopa-induced stimulation of FUS1 and RLM1 transcription [28].
• Finally, Mkk2p and Mpk1p also interacted in the two-hybrid assay [29].
• The ability of three mutant alleles of SLT2 generated by site-directed mutagenesis, namely E54 (glutamic acid), R54 (arginine) and F54 (phenylalanine), to complement slt2 mutants was tested [30].

References