PPIP5K1 interacts with the exocyst complex through a C-terminal intrinsically disordered domain and regulates cell motility

Machkalyan, Gayane; Trieu, Phan; Pétrin, Darlaine; Hébert, Terence E.; Miller, Greg

doi:10.1016/j.cellsig.2016.02.002

Cited by 32 publications

(25 citation statements)

References 76 publications

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“…Domain graphics are shown for the human PPIP5Ks used in this study (type 1, BC057395.1; type 2, XM_005271938). For PPIP5K1, amino acid residues defining each domain are numbered as in a previous study, which also defined the intrinsically disordered domain (IDR) (49). These boundaries were matched to those of the corresponding domains in PPIP5K2 by sequence alignments using Clustal Omega.…”

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confidence: 99%

The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis

Nguyen

Hofer

et al. 2017

Journal of Biological Chemistry

292

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Edited by Alex TokerPhosphate has multiple functions that direct the survival of all living organisms: in its organic form, P i is a component of genomic material, it serves as an energy currency, and it is ubiquitous in cell signaling. Thus, P i homeostasis is essential to life, but the mechanisms by which this occurs in humans and other metazoans are largely unknown (1, 2). Most of the previous work in this field of research has focused on yeast models (3-5). In particular, recent studies with Saccharomyces cerevisiae have revealed a new function in P i homeostasis for inositol pyrophosphates (5). The latter are soluble, intracellular signals that contain multiple phosphates and diphosphates; up to seven (InsP 7 ) 4 or eight (InsP 8 ) phosphates in total are crammed around a six-carbon inositol ring (see Refs. 6 -8 and Fig. 1). In S. cerevisiae, levels of one inositol pyrophosphate, 5-InsP 7 , track perturbations to P i homeostasis (5).This P i -sensing activity of 5-InsP 7 appears to reflect it being synthesized by a kinase class (kcs1 in yeast; IP6Ks in metazoans) that exhibits an unusually low affinity for ATP (9, 10). Consequently, cellular levels of 5-InsP 7 in yeast decrease in response to the drop in [ATP] that accompanies extracellular [P i ] depletion (5, 11). Furthermore, these ATP-driven changes in 5-InsP 7 levels appear to comprise a dynamic signaling response because 5-InsP 7 regulates proteins that maintain P i homeostasis through interactions with their SPX domains (5). However, it is not known to what extent this signaling response is applicable to metazoan cells, which lack orthologs of many of the yeast genes that function in P i sensing and P i homeostasis (2).

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confidence: 99%

The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis

Nguyen

Hofer

et al. 2017

Journal of Biological Chemistry

292

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“…We therefore cannot unambiguously conclude that it is the production of 1-PP-IP 7 that is the direct agent responsible for changes in apoptosis that we observe. We have recently reported that PPIP5K1 interacts with the exocyst complex and others have observed its localization at the plasma membrane in response to cell stimuli [24]. These observations suggest that PPIP5K1 acts at discrete sites and localized increases of InsPP may affect cellular processes without markedly affecting total cellular InsPP levels.…”

Section: Discussionmentioning

confidence: 89%

“…We have recently observed that PPIP5K1 interacts directly with components of the exocyst complex and is involved in the regulation of cellular motility [24]. The assembly of the exocyst complex is regulated by Ras-like GTPases, including RalA, which we also identified as a PPIP5K-interacting protein [26].…”

Section: Discussionmentioning

confidence: 99%

PPIP5K1 Suppresses Etoposide-triggered Apoptosis

Machkalyan

Hébert

Miller

2016

Journal of Molecular Signaling

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Inositol hexakisphosphate kinase 2 (IP6K2) potentiates pro-apoptotic signalling and increases the sensitivity of mammalian cells to cytotoxic agents. Diphosphoinositol pentakisphosphate kinase (PPIP5K) generates inositol pyrophosphates (InsPPs) that are structurally distinct from those produced by IP6K2 and their possible roles in affecting cell viability remain unclear. In the present study, we tested the impact of PPIP5K1 on cellular sensitivity to various genotoxic agents to determine if PPIP5K1 and IP6K2 contribute similarly to apoptosis. We observed that PPIP5K1 overexpression decreased sensitivity of cells toward several cytotoxic agents, including etoposide, cisplatin, and sulindac. We further tested the impact of PPIP5K1 overexpression on an array of apoptosis markers and observed that PPIP5K1 decreased p53 phosphorylation on key residues, including Ser-15, -46, and -392. Overexpression of a kinase-impaired PPIP5K1 mutant failed to protect cells from apoptosis, indicating this protection is a consequence PPIP5K1 catalytic activity, in contrast with the sensitivity conferred by IP6K2, which is dependent on both catalytic and non-catalytic functions. These observations reveal distinct roles for PPIP5K1 and IP6K2 and the InsPPs they produce in controlling cell death.

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“…The data in this article is the analysis of proteomic data of the interactions between PPIP5K1 and other cellular proteins [1] . Also included here are videos of the motility of HeLa cells with normal and decreased levels of PPIP5K1.…”

Section: Datamentioning

confidence: 99%

“…The potent actions of these phosphatases suggest these signals must be created near their sites of action. To identify sites where the inositol kinase, PPIP5K1 acts, we performed affinity purification of PPIP5K1 from HEK293 cells and analyzed these samples using mass spectrometry to identify the proteins pesent ( 10.1016/j.cellsig.2016.02.002 ) [1] . We further decreased PPIP5K1 levels in HeLa cells and treated these with PPIP5K1 siRNA.…”

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confidence: 99%

Mass spectrometry analysis of PPIP5K1 interactions and data on cell motility of PPIP5K1-deficient cells

et al. 2016

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Inositol pyrophosphates are cellular signals that are created by the actions of inositol kinases and are degraded by highly active inositol phosphatases. The potent actions of these phosphatases suggest these signals must be created near their sites of action. To identify sites where the inositol kinase, PPIP5K1 acts, we performed affinity purification of PPIP5K1 from HEK293 cells and analyzed these samples using mass spectrometry to identify the proteins pesent (10.1016/j.cellsig.2016.02.002) [1]. We further decreased PPIP5K1 levels in HeLa cells and treated these with PPIP5K1 siRNA. We then monitored the motility of these cells in Scratch assays.

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PPIP5K1 interacts with the exocyst complex through a C-terminal intrinsically disordered domain and regulates cell motility

Cited by 32 publications

References 76 publications

The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis

The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis

PPIP5K1 Suppresses Etoposide-triggered Apoptosis

Mass spectrometry analysis of PPIP5K1 interactions and data on cell motility of PPIP5K1-deficient cells

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