Intracellular localization of human Ins(1,3,4,5,6)<i>P</i>5 2-kinase

Brehm, Maria A.; Schenk, Tobias M. H.; Zhou, Xuefei; Fanick, Werner; Lin, Hongying; Windhorst, Sabine; Nalaskowski, Marcus M.; Kobras, Mario; Shears, Stephen B.; Mayr, Georg W.

doi:10.1042/bj20070382

Cited by 41 publications

(49 citation statements)

References 53 publications

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“…12 These cytoplasmic inclusions, referred to as stress granules, are observed in cells subjected to environmental stress, including heat, irradiation, oxidative conditions, and hyperosmolarity. 13 Because we observed increased intact IPP2K in the kidney and IPP2K urinary fragments, we examined whether stress granules are present in DN.…”

Section: Changes In Ipp2k and T Cell Intracellular Antigen 1 Expressimentioning

confidence: 99%

Urinary Peptidome May Predict Renal Function Decline in Type 1 Diabetes and Microalbuminuria

Merchant

Perkins

Boratyn

et al. 2009

Journal of the American Society of Nephrology

137

112

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One third of patients with type 1 diabetes and microalbuminuria experience an early, progressive decline in renal function that leads to advanced stages of chronic kidney disease and ESRD. We hypothesized that the urinary proteome may distinguish between stable renal function and early renal function decline among patients with type 1 diabetes and microalbuminuria. We followed patients with normal renal function and microalbuminuria for 10 to 12 yr and classified them into case patients (n ϭ 21) with progressive early renal function decline and control subjects (n ϭ 40) with stable renal function. Using liquid chromatography matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we identified three peptides that decreased in the urine of patients with early renal function decline [fragments of ␣1(IV) and ␣1(V) collagens and tenascin-X] and three peptides that increased (fragments of inositol pentakisphosphate 2-kinase, zona occludens 3, and FAT tumor suppressor 2). In renal biopsies from patients with early nephropathy from type 1 diabetes, we observed increased expression of inositol pentakisphosphate 2-kinase, which was present in granule-like cytoplasmic structures, and zona occludens 3. These results indicate that urinary peptide fragments reflect changes in expression of intact protein in the kidney, suggesting new potential mediators of diabetic nephropathy and candidate biomarkers for progressive renal function decline. 20: 206520: -207420: , 200920: . doi: 10.1681 Microalbuminuria (MA) has been the primary diagnostic test to identify patients who have type 1 diabetes and are at risk for overt proteinuria and subsequent declining renal function leading to ESRD 1,2 ; however, the predictive value of MA is now questioned. First, a large proportion of patients with MA can revert to normoalbuminuria 3-5 ; second, only a minority of patients with MA progress to proteinuria 3,6 ; and, third, in one third of patients with MA, progressive renal function decline starts already at the onset of MA, not proteinuria. The last process we refer to as early renal function decline (ERFD). 7 Our understanding of the disease process underlying ERFD is limited. The existing hypotheses about the cause of diabetic nephropathy (DN) are in question given that progressive ERFD is initiated J Am Soc Nephrol

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Section: Changes In Ipp2k and T Cell Intracellular Antigen 1 Expressimentioning

confidence: 99%

Urinary Peptidome May Predict Renal Function Decline in Type 1 Diabetes and Microalbuminuria

Merchant

Perkins

Boratyn

et al. 2009

Journal of the American Society of Nephrology

137

112

View full text Add to dashboard Cite

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“…In an earlier study we demonstrated that, in mammals, IP5K is predominantly a nuclear enzyme (Brehm et al, 2007). That observation has furthered general interest in understanding the significance of nuclear compartmentalization of inositol phosphate signaling (Martelli et al, 2011;Seeds et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…The source of the anti-IP5K antibody (used at 1:40 dilution) was as previously described (Brehm et al, 2007). Antibody specificity was validated by the loss of signal after RNAi against IP5K (supplementary material Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were prepared for analysis by confocal immunofluorescence as previously described (Brehm et al, 2007). The source of the anti-IP5K antibody (used at 1:40 dilution) was as previously described (Brehm et al, 2007).…”

Section: Methodsmentioning

confidence: 99%

“…Unlike siRNA of IP5K, which compromises both the catalytic and the scaffolding actions of IP5K (see above), we were able to separate these two functions in the overexpression paradigm; we used a catalytically dead IP5K C162Y construct (Brehm et al, 2007). This mutant kinase caused the UBF and TCOF1 to relocate out of the nucleolus to the same extent as did the wildtype IP5K (Fig.…”

Section: Evidence For a Structural Role For Ip5k In The Nucleolusmentioning

confidence: 99%

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A non-catalytic role for inositol 1,3,4,5,6-pentakisphosphate 2-kinase in the synthesis of ribosomal RNA

Brehm

Wundenberg

Williams

et al. 2013

Journal of Cell Science

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SummaryFundamental to the life and destiny of every cell is the regulation of protein synthesis through ribosome biogenesis, which begins in the nucleolus with the production of ribosomal RNA (rRNA). Nucleolar organization is a highly dynamic and tightly regulated process; the structural factors that direct nucleolar assembly and disassembly are just as important in controlling rRNA synthesis as are the catalytic activities that synthesize rRNA. Here, we report that a signaling enzyme, inositol 1,3,4,5,6-pentakisphosphate 2-kinase (IP5K) is also a structural component in the nucleolus. We demonstrate that IP5K has functionally significant interactions with three proteins that regulate rRNA synthesis: protein kinase CK2, TCOF1 and upstream-binding-factor (UBF). Through molecular modeling and mutagenic studies, we identified an Arg-Lys-Lys tripeptide located on the surface of IP5K that mediates its association with UBF. Nucleolar IP5K spatial dynamics were sensitive to experimental procedures (serum starvation or addition of actinomycin D) that inhibited rRNA production. We show that IP5K makes stoichiometrically sensitive contributions to the architecture of the nucleoli in intact cells, thereby influencing the degree of rRNA synthesis. Our study adds significantly to the biological significance of IP5K; previously, it was the kinase activity of this protein that had attracted attention. Our demonstration that IP5K 'moonlights' as a molecular scaffold offers an unexpected new example of how the biological sophistication of higher organisms can arise from gene products acquiring multiple functions, rather than by an increase in gene number.

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The Metabolism and the Functions of Diphosphoinositol Polyphosphates

Shears¹

2009

Handbook of Neurochemistry and Molecular Neurobiology

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Intracellular localization of human Ins(1,3,4,5,6)P5 2-kinase

Cited by 41 publications

References 53 publications

Urinary Peptidome May Predict Renal Function Decline in Type 1 Diabetes and Microalbuminuria

Urinary Peptidome May Predict Renal Function Decline in Type 1 Diabetes and Microalbuminuria

A non-catalytic role for inositol 1,3,4,5,6-pentakisphosphate 2-kinase in the synthesis of ribosomal RNA

The Metabolism and the Functions of Diphosphoinositol Polyphosphates

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