Response of the
            <i>Saccharomyces cerevisiae</i>
            Mpk1 Mitogen-Activated Protein Kinase Pathway to Increases in Internal Turgor Pressure Caused by Loss of Ppz Protein Phosphatases

Merchan, Stephanie; Bernal, Dolores; Serrano, Ramón; Yenush, Lynne

doi:10.1128/ec.3.1.100-107.2004

Cited by 114 publications

(149 citation statements)

References 31 publications

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“…This mutant has been previously shown to act in a dominant-negative manner to block the ubiquitination and degradation of CHIP substrates, such as the glucocorticoid receptor (36) and the cystic-fibrosis transmembrane conductance regulator (47). As expected from the above data, expression of Hsp70 greatly reduces the steady-state levels of T7-DLK in transfected cells (Fig.…”

Section: Chip Is Required For Hsp70-mediated Degradation Of Dlk-supporting

confidence: 73%

Down-regulation of the Mixed-lineage Dual Leucine Zipper-bearing Kinase by Heat Shock Protein 70 and Its Co-chaperone CHIP

et al. 2006

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Dual leucine zipper-bearing kinase (DLK) is a mixed-lineage kinase family member that acts as an upstream activator of the c-Jun N-terminal kinases. As opposed to other components of this pathway, very little is currently known regarding the mechanisms by which DLK is regulated in mammalian cells. Here we identify the stress-inducible heat shock protein 70 (Hsp70) as a negative regulator of DLK expression and activity. Support for this notion derives from data showing that Hsp70 induces the proteasomal degradation of DLK when both proteins are coexpressed in COS-7 cells. Hsp70-mediated degradation occurs with expression of wild-type DLK, which functions as a constitutively activated protein in these cells but not kinase-defective DLK. Interestingly, the Hsp70 co-chaperone CHIP, an E3 ubiquitin ligase, seems to be indispensable for this process since Hsp70 failed to induce DLK degradation in COS-7 cells expressing a CHIP mutant unable to catalyze ubiquitination or in immortalized fibroblasts derived from CHIP knock-out mice. Consistent with these data, we have found that endogenous DLK becomes sensitive to CHIP-dependent proteasomal degradation when it is activated by okadaic acid and that down-regulation of Hsp70 levels with an Hsp70 antisense attenuates this sensitivity. Therefore, our studies suggest that Hsp70 contributes to the regulation of activated DLK by promoting its CHIPdependent proteasomal degradation.Dual leucine zipper-bearing kinase (DLK) 2 is a serine/threonine kinase that belongs to a family of mitogen-activated protein kinase kinase kinases, known as mixed-lineage kinases (MLKs) (1). Members of this family, which also include MLK1, MLK2, MLK3, MLK4, leucine zipper-bearing kinase, and leucine zipper and sterile ␣-motif kinase (1), are characterized at the structural level by the presence of a catalytic domain bearing amino acid motifs found in serine/threonine and tyrosine kinases and one or two leucine zipper motifs, which regulate their activity by mediating protein dimerization or oligomerization (2-5). A number of other interesting motifs that are likely important for protein binding have also been identified in specific members of the MLK family. For instance, MLK2 and MLK3 contain a Src homology 3 (SH3) domain in their N-terminal region that binds, respectively, the GTPase dynamin and the Ste20-related protein kinase HPK1 (6, 7). Both MLK proteins also possess a functional Cdc42/Rac interactive binding (CRIB) motif that mediates association with Cdc42 and Rac1 in a GTP-dependent manner (8, 9).The importance of the MLKs as signaling molecules is highlighted by the fact that these proteins act as key regulators of the c-Jun N-terminal kinase (JNK) subgroup of mitogen-activated protein kinases (1). Specifically, all MLK family members regulate the JNK pathway by phosphorylating and activating the JNK direct upstream activators . In addition to their role in catalyzing JNK activation, MLKs are also known to contribute to apoptosis in neuronal cells. Indeed, when dominant negative forms of MLKs...

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Section: Chip Is Required For Hsp70-mediated Degradation Of Dlk-supporting

confidence: 73%

Down-regulation of the Mixed-lineage Dual Leucine Zipper-bearing Kinase by Heat Shock Protein 70 and Its Co-chaperone CHIP

et al. 2006

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“…In addition, the caffeine and CFW sensitivities of a strain lacking the Slt2 MAP kinase were also alleviated. The observation that the presence of the CaPpz1 protein can, at least in part, reverse the effects of the absence of ScPpz1 or mimic its overexpression with respect to both cation homeostasis and cell wall integrity is coherent, since it has been shown that these two phenotypes are interrelated (Merchan et al, 2004). The partial complementation of the Sch.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of ScPPZ1 suppresses the lytic phenotype of an slt2 mutant, whereas deletion of the ScPPZ1 gene or inhibition of its phosphatase activity results in a phenotype additive to that of the slt2 strain (de Nadal et al, 1998;Lee et al, 1993). The functional interaction between ScPpz1 and the CWI pathway has been explained on the basis of the combination of increased internal turgor pressure in Ppz-deficient strains and cell wall instability observed in strains lacking Slt2 (Merchan et al, 2004). Therefore, in budding yeast, the Ppz proteins play key roles in cation homeostasis, which is likely to affect cell cycle regulation.…”

Section: Introductionmentioning

confidence: 99%

Protein phosphatase CaPpz1 is involved in cation homeostasis, cell wall integrity and virulence of Candida albicans

et al. 2012

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“…Structurally similar to a RING finger domain, U-box-containing proteins are a third group of ubiquitin ligases with E3 activity that direct ubiquitylation of chaperone protein complex substrates, leading to increased degradation by the proteasome (24,26,48). CHIP was shown to promote ubiquitylation and degradation through the proteasome of GR (31), AR (13), and other proteins (26,49), including ErbB2/Neu (50,51). However, it was previously suggested that the predominant effect of CHIP on AR is inhibition of protein folding and reduced degradation (13).…”

Section: Discussionmentioning

confidence: 99%

An Androgen Receptor NH2-terminal Conserved Motif Interacts with the COOH Terminus of the Hsp70-interacting Protein (CHIP)

He¹,

Bai²,

Hnat³

et al. 2004

Journal of Biological Chemistry

122

113

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The NH 2 -terminal sequence of steroid receptors is highly variable between different receptors and in the same receptor from different species. In this study, a primary sequence homology comparison identified a 14-amino acid NH 2 -terminal motif of the human androgen receptor (AR) that is common to AR from all species reported, including the lower vertebrates. The evolutionarily conserved motif is unique to AR, with the exception of a partial sequence in the glucocorticoid receptor of higher species. The presence of the conserved motif in AR and the glucocorticoid receptor and its absence in other steroid receptors suggests convergent evolution. The function of the AR NH 2 -terminal conserved motif was suggested from a yeast two-hybrid screen that identified the COOH terminus of the Hsp70-interacting protein (CHIP) as a binding partner. We found that CHIP functions as a negative regulator of AR transcriptional activity by promoting AR degradation. In support of this, two mutations in the AR NH 2 -terminal conserved motif previously identified in the transgenic adenocarcinoma of mouse prostate model reduced the interaction between CHIP and AR. Our results suggest that the AR NH 2 -terminal domain contains an evolutionarily conserved motif that functions to limit AR transcriptional activity. Moreover, we demonstrate that the combination of comparative sequence alignment and yeast two-hybrid screening using short conserved peptides as bait provides an effective strategy to probe the structure-function relationships of steroid receptor NH 2 -terminal domains and other intrinsically unstructured transcriptional regulatory proteins.Steroid receptors depend on multiple domains for their function as ligand-dependent transcriptional activators. The DNAand ligand-binding domains have been studied extensively and have a high degree of structural and functional conservation. In contrast, the largely unstructured NH 2 -terminal domains (1-3) are highly variable in size and sequence, and the molecular mechanisms that contribute to transactivation are not well understood. The size of the NH 2 -terminal region of steroid receptors increases with evolutionary expansion (4, 5), from estrogen receptor-␣ (185 amino acid residues) to the glucocorticoid receptor (GR 1 ; 420 residues), androgen receptor (AR; 558 residues), progesterone receptor (B form; 566 residues), and mineralocorticoid receptor (602 residues). In contrast, transcription factors such as p53, NF-B, and VP16 typically have transcriptional activation domains of Ͻ100 residues.

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Response of the Saccharomyces cerevisiae Mpk1 Mitogen-Activated Protein Kinase Pathway to Increases in Internal Turgor Pressure Caused by Loss of Ppz Protein Phosphatases

Cited by 114 publications

References 31 publications

Down-regulation of the Mixed-lineage Dual Leucine Zipper-bearing Kinase by Heat Shock Protein 70 and Its Co-chaperone CHIP

Down-regulation of the Mixed-lineage Dual Leucine Zipper-bearing Kinase by Heat Shock Protein 70 and Its Co-chaperone CHIP

Protein phosphatase CaPpz1 is involved in cation homeostasis, cell wall integrity and virulence of Candida albicans

An Androgen Receptor NH2-terminal Conserved Motif Interacts with the COOH Terminus of the Hsp70-interacting Protein (CHIP)

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