TUSC4/NPRL2, a novel PDK1‐interacting protein, inhibits PDK1 tyrosine phosphorylation and its downstream signaling

Kurata, Atsuo; Katayama, Ryohei; Watanabe, Toshiki; Tsuruo, Takashi; Fujita, Naoya

doi:10.1111/j.1349-7006.2008.00874.x

Cited by 30 publications

(23 citation statements)

References 30 publications

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“…miR-409-5p has been shown to target STAG2, RSU1, NPRL2 and RBL2 (12). NPRL2 activates AKT pathway (39, 40) and RBL2 activates the E2F pathway (41). Thus, these miRNA activate oncogenic proteins by targeting tumor suppressors.…”

Section: Resultsmentioning

confidence: 99%

miR-154* and miR-379 in the DLK1-DIO3 MicroRNA Mega-Cluster Regulate Epithelial to Mesenchymal Transition and Bone Metastasis of Prostate Cancer

Gururajan

Josson

Chu

et al. 2014

Clinical Cancer Research

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Purpose MicroRNAs in the delta-like 1 homolog - deiodinase, iodothyronine 3 (DLK1-DIO3) cluster have been shown to be critical for embryonic development and epithelial to mesenchymal transition (EMT). DLK1-DIO3 cluster miRNAs are elevated in the serum of metastatic cancer patients. However, the biological functions of these miRNAs in the EMT and metastasis of cancer cells are poorly understood. We previously demonstrated the oncogenic and metastatic role of miR-409-3p/5p, a member of this cluster, in prostate cancer (PCa). In this study, we defined the role of miR-154* and miR-379, two key members of this cluster, in PCa progression and bone metastasis in both cell line models and clinical specimens. Experimental design Genetic manipulation of miR-154* and miR-379 was performed to determine their role in tumor growth, EMT and bone metastasis in mouse models. We determined the expression of miR-154* in prostate cancer clinical samples and bone metastasis samples using in situ hybridization and quantum dot labeling. Results Elevated expression of miR-154* and miR-379 was observed in bone metastatic PCa cell lines and tissues, and miR-379 expression correlated with PCa patient progression-free survival. Intracardiac inoculation (to mimic systemic dissemination) of miR-154* inhibitor-treated bone metastatic ARCaPM PCa cells in mice led to decreased bone metastasis and increased survival. Conclusion miR-154* and miR-379 play important roles in PCa biology by facilitating tumor growth, EMT and bone metastasis. This finding has particular translational importance since miRNAs in the DLK1-DIO3 cluster can be attractive biomarkers and possible therapeutic targets to treat bone metastatic PCa.

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Section: Resultsmentioning

confidence: 99%

miR-154* and miR-379 in the DLK1-DIO3 MicroRNA Mega-Cluster Regulate Epithelial to Mesenchymal Transition and Bone Metastasis of Prostate Cancer

Gururajan

Josson

Chu

et al. 2014

Clinical Cancer Research

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“…Growth factor stimulation leads to sequential phosphorylation of Tyr 9 and Tyr 373/376 (11,14,16,17), and substitutions for these phosphotyrosines result in decreased PDK1 activity (9,13,14,16,47). Previous studies showed that Pyk2 activates PDK1, but the mechanism was not determined (9,12,18).…”

Section: Discussionmentioning

confidence: 99%

PDK1 Recruitment to the SHPS-1 Signaling Complex Enhances Insulin-like Growth Factor-I-stimulated AKT Activation and Vascular Smooth Muscle Cell Survival

Shen

Radhakrishnan

et al. 2010

Journal of Biological Chemistry

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In vascular smooth muscle cells, exposed to hyperglycemia and insulin-like growth factor-I (IGF-I), SHPS-1 functions as a scaffold protein, and a signaling complex is assembled that leads to AKT activation. However, the underlying mechanism by which formation of this complex activates the kinase that phosphorylates AKT (Thr 308 ) is unknown. Therefore, we investigated the mechanism of PDK1 recruitment to the SHPS-1 signaling complex and the consequences of disrupting PDK1 recruitment for downstream signaling. Our results show that following IGF-I stimulation, PDK1 is recruited to SHPS-1, and its recruitment is mediated by Grb2, which associates with SHPS-1 via its interaction with Pyk2, a component of the SHPS-1-associated complex. A proline-rich sequence in PDK1 bound to an Src homology 3 domain in Grb2 in response to IGF-I. Disruption of Grb2-PDK1 by expression of either a Grb2 Src homology 3 domain or a PDK1 proline to alanine mutant inhibited PDK1 recruitment to SHPS-1, leading to impaired IGF-Istimulated AKT Thr 308 phosphorylation. Following its recruitment to SHPS-1, PDK1 was further activated via Tyr 373/376 phosphorylation, and this was required for a maximal increase in PDK1 kinase activity and AKT-mediated FOXO3a Thr 32 phosphorylation. PDK1 recruitment was also required for IGF-I to prevent apoptosis that occurred in response to hyperglycemia. Assembly of the Grb2-PDK1 complex on SHPS-1 was specific for IGF-I signaling because inhibiting PDK1 recruitment to SHPS-1 had no effect on EGF-stimulated AKT Thr 308 phosphorylation. These findings reveal a novel mechanism for recruitment of PDK1 to the SHPS-1 signaling complex, which is required for IGF-I-stimulated AKT Thr 308 phosphorylation and inhibition of apoptosis.AKT is phosphorylated at two key regulatory sites, Thr 308 in the activation loop of the catalytic domain and Ser 473 in the COOH-terminal domain. PDK1 (3-phosphoinositidedependent kinase 1) is the kinase responsible for phosphorylation of Thr 308 (1), and this is required for AKT-mediated inhibition of apoptosis (2-5). Although constitutive autophosphorylation of PDK1 Ser 241 is required for PDK1 kinase activity, it is not regulated by growth factors (1, 6). However, PDK1 activity is regulated by changes in its conformation, tyrosine phosphorylation, and subcellular localization (7-12). PDK1 undergoes tyrosine phosphorylation in response to insulin, angiotensin II, high glucose, and insulin-like growth factor-I (IGF-I) 2 (9,(11)(12)(13)(14)(15)(16)(17). Previous studies indicate that optimal activation of PDK1 requires phosphorylation of Tyr 373/376 (11,12,14,17), and growth factor receptor activation leads to PDK1 recruitment to the plasma membrane, followed by sequential phosphorylation of Tyr 9 and then Tyr 373/376 (14, 17). A previous study suggested that Pyk2 (proline-rich tyrosine kinase 2) plays an important role in PDK1 activation. Tanniyama et al. (9) showed that Pyk2 was required for optimal PDK1 tyrosine phosphorylation in response to angiotensin II and that Pyk2 and PDK1 were co...

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“…It may be possible that the NPRL2/3 human analogs perform similar functions to the yeast NPR2/3 proteins in conveying the amino acid signal to mTORC1. Interestingly, a recent study by Kuruta et al (57) demonstrated that NPRL2 interacted with and inhibited PDK1 (phosphoinositide-dependent kinase-1). PDK1 is upstream of the Akt/mTORC1 pathway (see Fig.…”

Section: Npr2 and Npr3mentioning

confidence: 96%

Leucine and mTORC1: a complex relationship

Dodd

Tee

2012

American Journal of Physiology-Endocrinology and Metabolism

215

183

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Amino acid availability is a rate-limiting factor in the regulation of protein synthesis. When amino acid supplies become restricted, mammalian cells employ homeostatic mechanisms to rapidly inhibit processes such as protein synthesis, which demands high levels of amino acids. Muscle cells in particular are subject to high protein turnover rates to maintain amino acid homeostasis. Mammalian target of rapamycin complex 1 (mTORC1) is an evolutionary conserved multiprotein complex that coordinates a network of signaling cascades and functions as a key mediator of protein translation, gene transcription, and autophagy. Signal transduction through mTORC1, which is centrally involved in muscle growth through enhanced protein translation, is governed by intracellular amino acid supply. The branched-chain amino acid leucine is critical for muscle growth and acts in part through activation of mTORC1. Recent research has revealed that mTORC1 signaling is coordinated primarily at the lysosomal membranes. This discovery has sparked a wealth of research in this field, revealing several different signaling molecules involved in transducing the amino acid signal to mTORC1, including the Rag GTPases, MAP4K3, and Vps34/ULK1. This review evaluates the current knowledge regarding cellular mechanisms that control and sense the intracellular amino acid pool. We discuss the role of leucine and mTORC1 in the regulation of amino acid transport via the system L and system A transporters such as LAT1 and SNAT2, as well as protein degradation via autophagic and proteasomal pathways. We also describe the complexities of energy homeostasis via AMPK and cell receptor-mediated growth signals that also converge on mTORC1. Leucine is a particularly potent regulator of protein turnover, to the extent where leucine stimulation alone is sufficient to stimulate mTORC1 signal transduction. The significance of leucine in this context is not yet known; however, recent advancements in this area will also be covered within this review.

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TUSC4/NPRL2, a novel PDK1‐interacting protein, inhibits PDK1 tyrosine phosphorylation and its downstream signaling

Cited by 30 publications

References 30 publications

miR-154* and miR-379 in the DLK1-DIO3 MicroRNA Mega-Cluster Regulate Epithelial to Mesenchymal Transition and Bone Metastasis of Prostate Cancer

miR-154* and miR-379 in the DLK1-DIO3 MicroRNA Mega-Cluster Regulate Epithelial to Mesenchymal Transition and Bone Metastasis of Prostate Cancer

PDK1 Recruitment to the SHPS-1 Signaling Complex Enhances Insulin-like Growth Factor-I-stimulated AKT Activation and Vascular Smooth Muscle Cell Survival

Leucine and mTORC1: a complex relationship

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