PIM1 Protein Kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells

Zhang, Fengxue; Beharry, Zanna; Harris, Thurl E.; Lilly, Michael B.; Smith, Charles D.; Mahajan, Sandeep; Kraft, Andrew S.

doi:10.4161/cbt.8.9.8210

Cited by 127 publications

(131 citation statements)

References 56 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…We further identify PRAS40 as a molecular link between A␤ accumulation and mTOR hyperactivity. Toward this end, when PRAS40 is phosphorylated by Akt or PIM-1 at Thr-246, it does not bind to mTOR and hence release its inhibitory effects on mTOR activity (14,15,65). Our data strongly support the conclusion that PRAS40 phosphorylation plays a key role in the A␤-induced mTOR hyperactivity.…”

Section: Discussionsupporting

confidence: 75%

“…The data presented suggest that the A␤-induced alteration in mTOR activity in the 7PA2 cells and in the 3xTg-AD mice may be mediated by PRAS40 phosphorylation, which is physiologically phosphorylated by Akt and by the protein kinase PIM-1 (64,65). To better understand the role of PRAS40 in the A␤-mediated mTOR hyperactivity, we injected concentrated FIGURE 4.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Caccamo¹,

Maldonado²,

Majumder³

et al. 2011

Journal of Biological Chemistry

161

132

View full text Add to dashboard Cite

Reducing the mammalian target of rapamycin (mTOR) activity increases lifespan and health span in a variety of organisms. Alterations in protein homeostasis and mTOR activity and signaling have been reported in several neurodegenerative disorders, including Alzheimer disease (AD); however, the causes of such deregulations remain elusive. Here, we show that mTOR activity and signaling are increased in cell lines stably transfected with mutant amyloid precursor protein (APP) and in brains of 3xTg-AD mice, an animal model of AD. In addition, we show that in the 3xTg-AD mice, mTOR activity can be reduced to wild type levels by genetically preventing A␤ accumulation. Similarly, intrahippocampal injections of an anti-A␤ antibody reduced A␤ levels and normalized mTOR activity, indicating that high A␤ levels are necessary for mTOR hyperactivity in 3xTg-AD mice. We also show that the intrahippocampal injection of naturally secreted A␤ is sufficient to increase mTOR signaling in the brains of wild type mice. The mechanism behind the A␤-induced mTOR hyperactivity is mediated by the proline-rich Akt substrate 40 (PRAS40) as we show that the activation of PRAS40 plays a key role in the A␤-induced mTOR hyperactivity. Taken together, our data show that A␤ accumulation, which has been suggested to be the culprit of AD pathogenesis, causes mTOR hyperactivity by regulating PRAS40 phosphorylation. These data further indicate that the mTOR pathway is one of the pathways by which A␤ exerts its toxicity and further support the idea that reducing mTOR signaling in AD may be a valid therapeutic approach.Amyloid plaques and neurofibrillary tangles are hallmark neuropathological lesions of Alzheimer disease (AD), 3 the most common form of neurodegenerative disorder (1). Neurofibrillary tangles are intracellular inclusions formed of hyperphosphorylated Tau (2-4). Plaques are extracellular inclusions mainly formed of a small peptide called amyloid-␤ (A␤) (5, 6). Clinically, AD is characterized by profound memory loss and cognitive dysfunction (7). Growing evidence is converging on soluble A␤ as a mediator of early cognitive decline in AD (8, 9). Although the molecular mechanisms underlying A␤-induced cognitive decline remain elusive, soluble A␤ oligomers have been shown to alter signal transduction pathways that are key for learning and memory, suggesting that alterations in such pathways may underlie the onset of cognitive decline in AD (10).The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that forms two multiprotein complexes known as mTOR complex (mTORC) 1 and 2 (11). mTORC1 controls protein homeostasis; its activity is inhibited by rapamycin, and it contains mTOR, raptor, proline-rich Akt substrate 40 kDa (PRAS40), and mLT8. mTORC2, which is insensitive to rapamycin, controls cellular shape by modulating actin function and contains mTOR, rictor, mLST8, and hSIN (11, 12). In mTORC1, raptor binds to mTOR substrates and is necessary for mTOR activity (13). PRAS40 is another mTOR regulatory protein, which inhibits mTOR...

show abstract

Section: Discussionsupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Caccamo¹,

Maldonado²,

Majumder³

et al. 2011

Journal of Biological Chemistry

161

132

View full text Add to dashboard Cite

show abstract

“…Importantly, Pim kinases show similar substrate specificity as AKT. For example, a recent study revealed that overexpression of Pim-1 increased PRAS40 phosphorylation at Thr246, an AKT phosphorylation site (Zhang et al, 2009). In this study, we observed that Pim deficiency reduced PRAS40 phosphorylation at Thr246 in v-Abl transformants (Supplementary Figure S7).…”

Section: Discussionsupporting

confidence: 67%

Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells

et al. 2010

View full text Add to dashboard Cite

“…[30][31][32][33] Most recent work suggests that phosphorylation of the proline-rich Akt substrate 1 (PRAS1) might also have the potential to block apoptosis of murine factor-dependent hematopoietic progenitor cells (FDCP-1). 34 In addition, PIM1 seem to impair the activity of the apoptosis signaling kinase 1 (ASK1), by direct phosphorylation, resulting in protection from H2O2-induced cell death of H1299 lung cancer cells. 35 Intriguingly, overexpression of PIM1 also stimulated cell death signaling in Rat1 fibroblasts elicited by c-MYC most probably through interaction and modification of the Cdc25A cell cycle phosphatase.…”

mentioning

confidence: 99%

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Brault¹,

Gasser²,

Bracher³

et al. 2010

Haematologica

335

413

View full text Add to dashboard Cite

The online version of this article has a Supplementary Appendix.The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials. Haematologica 2010;95:1004-1015. doi:10.3324/haematol.2009 This is an open-access paper. ABSTRACTin blast crisis. 6 Abundant levels of PIM1 were found in hematopoietic cells. Moreover, sustained PIM1 expression was induced by cytokines that signal through structurally related receptors such as IL-3, GM-CSF, G-CSF or Subsequently, several studies have documented that PIM1 is a major downstream target of the signal transducer and activator of transcription (STATs) induced by a large variety of additional receptors such as IL-2, IL-7, IL-9, IFNγ, EPO, FLT3 or TPO.7 PIM1 expression is not only regulated at the transcriptional, but also at the posttranscriptional, translational and posttranslational levels ( Figure 1). Other studies have shown that PIM1 kinase is significantly protected from proteasomal degradation by heat shock proteins (Hsp70, Hsp90). 8,9 Moreover, it has been proposed that micro-RNAs, miR-1 and miR-210, might be implicated in regulation of PIM1 expression. 10,11 Germline inactivation of the PIM1 gene was associated with a mild phenotype as PIM1 deficient mice are ostensibly normal, healthy and fertile. However, subtle functional defects of the hematopoietic system have been identified: PIM1 -/-mice showed erythrocytic microcytosis and PIM1-/-B cells and bone marrow-derived mast c...

show abstract

PIM1 Protein Kinase regulates PRAS40 phosphorylation and mTOR activity in FDCP1 cells

Cited by 127 publications

References 56 publications

Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Contact Info

Product

Resources

About