The Molecular Chaperone Hsp70 Activates Protein Phosphatase 5 (PP5) by Binding the Tetratricopeptide Repeat (TPR) Domain

Connarn, Jamie; Assimon, Victoria A.; Reed, Rebecca A.; Tse, Eric; Southworth, Daniel R.; Zuiderweg, Erik R. P.; Gestwicki, Jason E.; Sun, Duxin

doi:10.1074/jbc.m113.519421

Cited by 37 publications

(23 citation statements)

References 41 publications

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“…The interactions of MtSerB2 with these HSPs can have broad implications as the chaperone activities of HSP90 and HSP70 are steered by interactions with co-chaperones and this The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins and is inhibited… directs their activity toward specific clients. HSPs 90 and 70 are known to bind and increase the activity of phosphatases that in turn carry out multi-site dephosphorylation of HSP bound clients [40,41]. In this study we have shown that MtSerB2 mediates the dephosphorylation of various host proteins.…”

Section: Discussionmentioning

confidence: 73%

The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins and is inhibited by Clofazimine

Shree

Singh

Saxena

et al. 2016

Cell. Mol. Life Sci.

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Mycobacterium tuberculosis codes for a HAD-phosphatase, Rv3042c (MtSerB2), that has earlier been characterized as a metabolic enzyme. Here we demonstrate that MtSerB2 is secreted into the cytosol of infected macrophages and is found in bronchoalveolar lavage samples of tuberculosis patients. MtSerB2 induces significant cytoskeleton rearrangements through cofilin activation and affects the expression of genes that regulate actin dynamics. It specifically interacts with HSP90, HSP70 and HSP27 that block apoptotic pathways and not with other HSPs. It actively dephosphorylates MAPK-p38 and NF-kappa B p65 that play crucial roles in inflammatory and immune responses. This in turn leads to down-regulation of Interleukin 8, a chemotactic and inflammatory cytokine. Finally, during evaluation of inhibitors against MtSerB2 we found that Clofazimine, a drug being evaluated for XDR and MDR tuberculosis, inhibits MtSerB2 phosphatase activity and reverses the above effects and interactions with host proteins. Overall, the study identifies that MtSerB2 has new functions that might help the pathogen to evade the host's immune response.

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Section: Discussionmentioning

confidence: 73%

The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins and is inhibited by Clofazimine

Shree

Singh

Saxena

et al. 2016

Cell. Mol. Life Sci.

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“…Structural analysis has revealed that PP5 contains a C-terminal catalytic domain and three N-terminal tetratricopeptide repeats (TPRs) that are unique in the phosphoprotein phosphatase family (10). PP5 is auto-inhibited by intramolecular interactions with its TPR domain (11).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of protein phosphatase 5 inhibits ovarian cancer growth in vitro

et al. 2015

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Abstract. Ovarian cancer is the most common cause of gynecological cancer-related mortality. Serine/threonine protein phosphatase 5 (PP5, PPP5C) has been recognized to be involved in the regulation of multiple cellular signaling cascades that control diverse cellular processes, including cell growth, differentiation, proliferation, motility and apoptosis. In this study, to evaluate the functional role of PP5 in ovarian cancer cells, lentivirus-mediated RNA interference (RNAi) was applied to silence PPP5C in the human ovarian cancer cell line CAOV-3. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell colony forming ability was measured by colony formation. Cell cycle progression was determined by propidium iodide staining and flow cytometry. The results demonstrated that lentivirus-mediated RNAi specifically suppressed the expression of PPP5C at the mRNA and protein levels in CAOV-3 cells. Further investigations revealed that PP5 knockdown significantly inhibited the proliferation and colony formation of CAOV-3 cells. Moreover, the cell cycle of CAOV-3 cells was arrested at the G0/G1 phase following PP5 knockdown. This study highlights the crucial role of PP5 in promoting ovarian cancer cell proliferation, and provides a foundation for further study into the clinical potential of lentiviral-mediated delivery of PP5 RNAi therapy for the treatment of ovarian cancer. IntroductionOvarian cancer is the most common invasive malignancy of the female genital tract in the USA, with an estimated 22,240 cases diagnosed annually. Approximately 14,030 females succumb every year to ovarian cancer, representing the most common cause of mortality among females with gynecological malignancies (1). Surgical resection and platinum-based combination regimens offer a modest but significant survival advantage in ovarian cancer patients with advanced or metastatic disease, although most patients eventually experience disease progression (2). These data highlight the need to identify new approaches that, along with the current treatments, may assist in bringing about a better outcome for ovarian cancer patients.Protein kinases and phosphatases work together to control cellular processes and signaling pathways (3,4). Although much more is known about protein kinases and their relevant substrates compared with protein phosphatases (5-7), the significance of studying protein phosphatase enzymes and their targets has been demonstrated for disease states attributed in part to malfunctioning protein phosphatase enzymes (8). Protein phosphatase 5 (PP5; gene name, PPP5C) is a ubiquitously expressed serine/threonine protein phosphatase related to PP1, PP2A and PP2B (9). Structural analysis has revealed that PP5 contains a C-terminal catalytic domain and three N-terminal tetratricopeptide repeats (TPRs) that are unique in the phosphoprotein phosphatase family (10). PP5 is auto-inhibited by intramolecular interactions with its TPR domain (11).PP5 has been implicated in numerous cellular processe...

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“…2b). These proteins, including protein phosphatase 5 (PP5), Hsc70-organizing protein (HOP), and the C-terminal Hsc70-interacting protein (CHIP), bind to the C-terminal EEVD motif that is located at the end of Hsp70's lid [59][60][61][62]. Rather than impacting ATP cycling, the TPR co-chaperones appear to coordinate "hand-off" of Hsp70's clients to other pathways.…”

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confidence: 96%

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

Srinivasan

Shao

et al. 2015

Topics in Medicinal Chemistry

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Cancer cells survive in the presence of stresses that would normally cause cell death. To accomplish this feat, they express elevated levels of the molecular chaperones: heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90). Knockdown of these chaperones is selectively toxic to cancer cells, suggesting that they might be promising nodes for anticancer therapy. However, while inhibitors of Hsp90 are well known, progress in the development of Hsp70 inhibitors has proven more difficult. Hsp70 binds tightly to ATP through a highly conserved domain of the actin/hexokinase superfamily, making it challenging to identify selective, competitive inhibitors. Despite this obstacle, progress has been made and first-generation molecules are being deployed. To supplement these efforts, compounds that target important allosteric sites on the chaperone have also been discovered. In some of these cases, the molecules have been shown to control key protein-protein interactions between Hsp70 and its co-chaperones. In other cases, allosteric sites have been used to gain unexpected selectivity for members of the Hsp70 family. Here, we review recent progress in the development of Hsp70 inhibitors.

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The Molecular Chaperone Hsp70 Activates Protein Phosphatase 5 (PP5) by Binding the Tetratricopeptide Repeat (TPR) Domain

Cited by 37 publications

References 41 publications

The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins and is inhibited by Clofazimine

The M. tuberculosis HAD phosphatase (Rv3042c) interacts with host proteins and is inhibited by Clofazimine

Knockdown of protein phosphatase 5 inhibits ovarian cancer growth in vitro

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

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