The C‐terminus of human glutaminase L mediates association with PDZ domain‐containing proteins<sup>1</sup>

Olalla, Lucı́a; Aledo, Juan Carlos; Bannenberg, Gerard; Márquez, Javier

doi:10.1016/s0014-5793(00)02373-5

Cited by 60 publications

(71 citation statements)

References 39 publications

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“…The mechanism by which LGA enters the nucleus at present is unclear because LGA lacks any known targeting signal specific for the nucleus. However, recent findings have established the importance of PDZ domain-containing proteins in localization to the nucleus (20 -23), and we have reported the ability of the C terminus of LGA to mediate its association with PDZ domain-containing proteins (24). Therefore, it is tempting to speculate that LGA may reach the nucleus through interactions with other proteins, although this hypothesis remains to be explored.…”

Section: Discussionmentioning

confidence: 90%

Nuclear Localization of L-type Glutaminase in Mammalian Brain

Olalla¹,

Gutiérrez²,

Campos³

et al. 2002

Journal of Biological Chemistry

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In mammals, there are two different genes encoding for glutaminase isoforms, named liver (LGA) and kidney (KGA) types. LGA has long been believed to be present only in liver mitochondria from adult animals. However, we have recently reported the presence of LGA mRNA in human brain. We now describe the expression of LGA mRNA in the brain of other mammals (cow, mouse, rabbit, and rat) and in different areas of human brain as assessed by Northern blot analysis. The presence of mRNA encoding for this isoform in rat brain was further confirmed by reverse transcriptase-PCR cloning and sequencing. Although it has been well accepted that glutaminase is a mitochondrial enzyme, using newly generated isoform-specific antibodies, we have found a differential intracellular immunolocalization of both glutaminase isoforms in rat and monkey brain. In both species, KGA protein was present in mitochondria, whereas LGA protein was localized in nuclei. Furthermore, subcellular fractionation and Western blot analysis revealed that brain LGA was enriched in nuclei where it was catalytically active. Nuclear glutaminase exhibited a kinetic behavior that resembles that of the liver-type enzyme with regard to the low phosphate concentration requirement; however, nuclear glutaminase was susceptible to glutamate inhibition, a property that is absent in the rat liver enzyme.

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Section: Discussionmentioning

confidence: 90%

Nuclear Localization of L-type Glutaminase in Mammalian Brain

Olalla¹,

Gutiérrez²,

Campos³

et al. 2002

Journal of Biological Chemistry

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“…The single PDZ domain of TIP-1 is located centrally and flanked by short Nand C-terminal sequences (22,23). Various deletion mutants of TIP-1 were tested in an in vivo interaction assay with coexpressed ␤-catenin, and the obtained results clearly demonstrated the requirement of the intact PDZ domain for complex formation ( Fig.…”

Section: Tip-1 Binds ␤-Catenin Via Its Pdz Domain-tip-1 Belongs To Thmentioning

confidence: 89%

“…TIP-1 has been first identified in a yeast two-hybrid screen as a Tax-interacting protein (22), and recent work has shown that it can also bind glutaminase L and rhotekin (23,24). Human and mouse TIP-1 are highly similar small proteins (14 kDa) that seem to be involved in the Rho signaling pathway (24).…”

Section: ␤-Cateninmentioning

confidence: 99%

The PDZ Protein Tax-interacting Protein-1 Inhibits β-Catenin Transcriptional Activity and Growth of Colorectal Cancer Cells

Kanamori¹,

Sandy

Marzinotto

et al. 2003

Journal of Biological Chemistry

115

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Wnt signaling is essential during development while deregulation of this pathway frequently leads to the formation of various tumors including colorectal carcinomas. A key component of the pathway is ␤-catenin that, in association with TCF-4, directly regulates the expression of Wnt-responsive genes. To identify novel binding partners of ␤-catenin that may control its transcriptional activity, we performed a mammalian twohybrid screen and isolated the Tax-interacting protein (TIP-1). The in vivo complex formation between ␤-catenin and TIP-1 was verified by coimmunoprecipitation, and a direct physical association was revealed by glutathione S-transferase pull-down experiments in vitro. By using a panel of deletion mutants of both proteins, we demonstrate that the interaction is mediated by the PDZ (PSD-95/DLG/ZO-1 homology) domain of TIP-1 and requires primarily the last four amino acids of ␤-catenin. TIP-1 overexpression resulted in a dose-dependent decrease in the transcriptional activity of ␤-catenin when tested on the TOP/FOPFLASH reporter system. Conversely, siRNA-mediated knock-down of endogenous TIP-1 slightly increased endogenous ␤-catenin transactivation function. Moreover, we show that overexpression of TIP-1 reduced the proliferation and anchorageindependent growth of colorectal cancer cells. These data suggest that TIP-1 may represent a novel regulatory element in the Wnt/␤-catenin signaling pathway.

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“…Two PDZ domain-containing proteins were isolated: alpha-syntrophin (SNT) and Glutaminase-Interacting Protein (GIP) (69). Human GAB has been endowed with consensus protein motifs and domains that might support its role as a multifunctional protein (1).…”

Section: Other Ga Functions In Mammalian Brainmentioning

confidence: 99%

Brain glutaminases

Márquez

Martín-Rufián

Segura

et al. 2010

BioMolecular Concepts

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Glutaminase is considered as the main glutamate producer enzyme in brain. Consequently, the enzyme is essential for both glutamatergic and gabaergic transmissions. Glutaminederived glutamate and ammonia, the products of glutaminase reaction, fulfill crucial roles in energy metabolism and in the biosynthesis of basic metabolites, such as GABA, proteins and glutathione. However, glutamate and ammonia are also hazardous compounds and danger lurks in their generation beyond normal physiological thresholds; hence, glutaminase activity must be carefully regulated in the mammalian brain. The differential distribution and regulation of glutaminase are key factors to modulate the metabolism of glutamate and glutamine in brain. The discovery of novel isoenzymes, protein interacting partners and subcellular localizations indicate new functions for brain glutaminase. In this short review, we summarize recent findings that point consistently towards glutaminase as a multifaceted protein able to perform different tasks. Finally, we will highlight the involvement of glutaminase in pathological states and its consideration as a potential therapeutic target.

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The C‐terminus of human glutaminase L mediates association with PDZ domain‐containing proteins¹

Cited by 60 publications

References 39 publications

Nuclear Localization of L-type Glutaminase in Mammalian Brain

Nuclear Localization of L-type Glutaminase in Mammalian Brain

The PDZ Protein Tax-interacting Protein-1 Inhibits β-Catenin Transcriptional Activity and Growth of Colorectal Cancer Cells

Brain glutaminases

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The C‐terminus of human glutaminase L mediates association with PDZ domain‐containing proteins1

Cited by 60 publications

References 39 publications

Nuclear Localization of L-type Glutaminase in Mammalian Brain

Nuclear Localization of L-type Glutaminase in Mammalian Brain

The PDZ Protein Tax-interacting Protein-1 Inhibits β-Catenin Transcriptional Activity and Growth of Colorectal Cancer Cells

Brain glutaminases

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The C‐terminus of human glutaminase L mediates association with PDZ domain‐containing proteins¹