Search results for FH

Showing 24 results out of 158

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Protein (5 results from a total of 23)

FH

Identifier: R-HSA-70980
Species: Homo sapiens
Compartment: mitochondrial matrix
Primary external reference: UniProt: FH: P07954
Identifier: R-HSA-2425392
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: IRS1: P35568
Identifier: R-HSA-1838987
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: CPSF6: Q16630
Identifier: R-HSA-1838998
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: FGFR1OP2: Q9NVK5
Identifier: R-HSA-1614368
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: CPSF6: Q16630

Complex (5 results from a total of 10)

Identifier: R-HSA-451041
Species: Homo sapiens
Compartment: mitochondrial matrix
Identifier: R-HSA-6807075
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-6807085
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-8850845
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-1637878
Species: Homo sapiens
Compartment: cytosol

Reaction (5 results from a total of 103)

Identifier: R-HSA-70982
Species: Homo sapiens
Compartment: mitochondrial matrix
Mitochondrial fumarate hydratase (FH) tetramer catalyzes the reversible reaction of fumarate and water to form malate, the seventh step of the TCA cycle (Ajalla Aleixo et al., 2019; Wang et al., 2020). Mutations in the FH gene can lead to fumarase deficiency (FMRD, MIM:606812) or to leiomyomatosis and renal cell cancer (HLRCC, MIM:150800) (Bourgeron et al., 1994; reviewed by Giallongo et al, 2023).
Identifier: R-HSA-9717841
Species: Homo sapiens
Compartment: cytosol
The mevalonate pathway is responsible for the biosynthesis of all isoprenoids, metabolites that are vital for normal cellular functions. Two key isoprenoids, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are responsible for the post-translational prenylation of small GTP-binding proteins, and serve as the biosynthetic precursors to numerous other biomolecules. The downstream metabolite of FPP and GGPP is squalene, the precursor to steroids, bile acids, lipoproteins, and vitamin D.

Nitrogen-containing bisphosphonates (NBPs) are drugs used to treat diseases characterized by excessive bone resorption such as Paget's disease of bone, bone metastases, multiple myeloma (Simoni et al. 2008), and osteoporosis. NBPs act by inhibiting farnesyl pyrophosphate synthase (FDPS) involved in the mevalonate pathway (Bergstrom et al. 2000, Dunford et al. 2001, Dunford et al. 2008, Räikkönen et al. 2011). Inhibition of FDPS in osteoclasts prevents the biosynthesis of the isoprenoid lipids FPP and GGPP, which are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is primarily due to the loss of geranylgeranylated small GTPases (Review - Cremers et al. 2019). Approved NBPs include the second generation NBPs pamidronic acid and alendronic acid and the third generation NBPs ibandronic acid, zoledronic acid, minodronic acid and risedronate.
Identifier: R-HSA-9698754
Species: Homo sapiens
Compartment: nucleoplasm
Tyrosine phosphorylated STAT5 binds to target interferon gamma activated sequence (GAS) elements in the promoters of the NOX4 gene in response to signaling by FLT3 ITD mutants. NOX4 expression increases the production of reactive oxygen species, causing the oxidative inactivation of the protein phosphatase PTPRJ (also known as DEP1). As a result, FTL3 ITD mutants exhibit increased signaling, proliferation and transformation relative to WT FLT3 cells (Jayavelu et al 2016a; Godfrey et al, 2012; Kresinsky et al, 2015; reviewed in Jayavelu et al, 2016b).
Identifier: R-HSA-9698758
Species: Homo sapiens
Compartment: plasma membrane
NOX4 catalyzes the synthesis of H2O2 downstream of FLT3 ITD mutants in a STAT5-dependent manner, increasing the levels of reactive oxygen species (ROS) (Jayvavelu et al, 2016a; Sallmyer et al, 2008; Reddy et al, 2011). High ROS levels cause oxidative inactivation of the protein tyrosine phosphatase PTPRJ, also known as DEP1, a negative regulator of FLT3 signaling. In consequence, FLT3 ITD-expressing cells have higher signaling activity than the wild type, as well as increased proliferation (Arora et al, 2011; Godfrey et al, 2012; Kresinsky et al, 2015; Jayavelu et al, 2016a; reviewed in Jayavelu et al, 2016b).
Identifier: R-HSA-9698762
Species: Homo sapiens
Compartment: nucleoplasm, plasma membrane
NOX4 expression is upregulated in a FLT3 ITD- and STAT5-dependent manner relative to levels in wild type cells. NOX4 expression increases production of reactive oxygen species, resulting in the inhibition of the catalytic site of the FLT3 negative regulator PTPRJ (also known as DEP1). As a consequence, FLT3 ITD mutants show enhance signaling, proliferation and colony forming ability (Arora et al, 2011; Godfrey et al, 2012; Kesinsky et al, 2015; Jayavelu et al, 2016; reviewed in Jayavelu et al, 2016).

Pathway (5 results from a total of 18)

Identifier: R-HSA-6807070
Species: Homo sapiens
PTEN is regulated at the level of gene transcription, mRNA translation, localization and protein stability.

Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016).

MicroRNAs miR-26A1, miR-26A2, miR-22, miR-25, miR-302, miR-214, miR-17-5p, miR-19 and miR-205 bind PTEN mRNA and inhibit its translation into protein. These microRNAs are altered in cancer and can account for changes in PTEN levels (Meng et al. 2007, Xiao et al. 2008, Yang et al. 2008, Huse et al. 2009, Kim et al. 2010, Poliseno, Salmena, Riccardi et al. 2010, Cai et al. 2013). In addition, coding and non-coding RNAs can prevent microRNAs from binding to PTEN mRNA. These RNAs are termed competing endogenous RNAs or ceRNAs. Transcripts of the pseudogene PTENP1 and mRNAs transcribed from SERINC1, VAPA and CNOT6L genes exhibit this activity (Poliseno, Salmena, Zhang et al. 2010, Tay et al. 2011, Tay et al. 2014).

PTEN can translocate from the cytosol to the nucleus after undergoing monoubiquitination. PTEN's ability to localize to the nucleus contributes to its tumor suppressive role (Trotman et al. 2007). The ubiquitin protease USP7 (HAUSP) targets monoubiquitinated PTEN in the nucleus, resulting in PTEN deubiquitination and nuclear exclusion. PML, via an unknown mechanism that involves USP7- and PML-interacting protein DAXX, inhibits USP7-mediated deubiquitination of PTEN, thus promoting PTEN nuclear localization. Disruption of PML function in acute promyelocytic leukemia, through a chromosomal translocation that results in expression of a fusion protein PML-RARA, leads to aberrant PTEN localization (Song et al. 2008).

Several ubiquitin ligases, including NEDD4, WWP2, STUB1 (CHIP), RNF146, XIAP and MKRN1, polyubiquitinate PTEN and target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Ahmed et al. 2011, Maddika et al. 2011, Lee et al. 2015, Li et al. 2015). The ubiquitin proteases USP13 and OTUD3, frequently down-regulated in breast cancer, remove polyubiquitin chains from PTEN, thus preventing its degradation and increasing its half-life (Zhang et al. 2013, Yuan et al. 2015). The catalytic activity of PTEN is negatively regulated by PREX2 binding (Fine et al. 2009, Hodakoski et al. 2014) and TRIM27-mediated ubiquitination (Lee et al. 2013), most likely through altered PTEN conformation.

In addition to ubiquitination, PTEN also undergoes SUMOylation (Gonzalez-Santamaria et al. 2012, Da Silva Ferrada et al. 2013, Lang et al. 2015, Leslie et al. 2016). SUMOylation of the C2 domain of PTEN may regulate PTEN association with the plasma membrane (Shenoy et al. 2012) as well as nuclear localization of PTEN (Bassi et al. 2013, Collaud et al. 2016). PIASx-alpha, a splicing isorom of E3 SUMO-protein ligase PIAS2 has been implicated in PTEN SUMOylation (Wang et al. 2014). SUMOylation of PTEN may be regulated by activated AKT (Lin et al. 2016). Reactions describing PTEN SUMOylation will be annotated when mechanistic details become available.

Phosphorylation affects the stability and activity of PTEN. FRK tyrosine kinase (RAK) phosphorylates PTEN on tyrosine residue Y336, which increases PTEN half-life by inhibiting NEDD4-mediated polyubiquitination and subsequent degradation of PTEN. FRK-mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).

PTEN localization and activity are affected by acetylation of its lysine residues (Okumura et al. 2006, Ikenoue et al. 2008, Meng et al. 2016). PTEN can undergo oxidation, which affects its function, but the mechanism is poorly understood (Tan et al. 2015, Shen et al. 2015, Verrastro et al. 2016).

Identifier: R-HSA-8943724
Species: Homo sapiens
Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016).
Identifier: R-HSA-9759475
Species: Homo sapiens
CDH11 gene encodes Cadherin-11, also known as osteoblast cadherin (OB-cadherin). The CDH11 gene maps to chromosome 16, chromosomal band 16q22, which is a subject to recurrent genomic loss in some types of cancer. The CDH11 gene consists of 14 exons, which are known to encode two splicing isoforms. Both splicing isoforms are expressed in the heart, brain, placenta, lung and bone, but not in the kidney, skeletal muscle, pancreas and liver (Okazaki et al. 1994; Kawaguchi et al. 1999). Several transcription factors have been shown to directly regulate CDH11 gene transcription, including HOXC8 (Lei et al. 2005; Lei et al. 2006; Li et al. 2014), ILF3 (Zhang et al. 2017), ZEB2 (Nam et al. 2012; Nam et al. 2014), HEYL (Liu et al. 2020), FOXF1 (Black et al. 2018), and BHLHE22 (Ross et al. 2012), and the transcription of CDH11 has also been shown to be influenced by a number of growth factors and hormones, such as FGF2 (Strutz et al. 2002; James et al. 2008), TNF (Wu et al. 2013), TGFB1 (Schneider et al. 2012; Schulte et al. 2013; Hahn et al. 2016; Cheng et al. 2018; Ruan et al. 2019; Doolin et al. 2021; Wilson et al. 2022), TGFB2 (Wecker et al. 2013; Theodossiou et al. 2019), GNRH1 (Peng et al. 2015), PTH (Yao et al. 2014), dexamethasone (Lecanda et al. 2000), and progesterone (Chen et al. 1999). CDH11 can also affect TGFB1 signaling, thereby possibly creating a feedback loop (Passanha et al. 2022). Expression of mouse Cdh11 in mouse osteoblast-like cell line (MC3T3-E1) is not affected by osteogenic hormones triiodothyronine (T3) and 1,25-dihydroxyvitamin D3 at either mRNA or protein levels (Leugmayr et al. 2000). CDH11 mRNA has been identified as the target of several microRNAs, such as miR-200c-3p (Luo et al. 2013; Van der Goten et al. 2014) and miR-451a (Yamada et al. 2018; Wang et al. 2020; Wang et al. 2021).

Like other classical cadherins, CDH11 associates with several catenin proteins through its intracellular domain, which is thought to play a role in the establishment and regulation of adherens junctions: CTNND1 (also known as p120 catenin or delta-catenin), CTNNB1 (beta-catenin), JUP (Junction Plakoglobin, also known as gamma-catenin), and CTNNA1 (alpha-catenin) (Straub et al. 2003; Kiener et al. 2006; Ortiz et al. 2015; Lee et al. 2018).

CDH11, through its C-terminus, also forms a complex with angiomotin (AMOT) isoform p80 (AMOT-2), which is implicated in CDH11-mediated cell migration and tumor cell invasiveness (Levchenko et al. 2004; Jiang et al. 2006; Yi et al. 2011; Oritz et al. 2015; Lee et al. 2018).

Through its extracellular region, CDH11 binds to the C-terminal fragment of ANGPTL4 (Angiopoietin-like-4), commonly known as cANGPTL4, which is implicated in the regulation of wound healing. The variant isoform of CDH11 (CDH11v), an 85 kDa membrane-bound fragment produced as a consequence of alternative splicing (Kawaguchi et al. 1999), can compete with the canonical CDH11 for cANGPTL4 binding, leading to diminished CTNNB1 release (Teo et al. 2017).

During normal development, CDH11 is implicated as a regulator of stem cell fate decisions, especially in mesodermal cell lineages (reviewed in Alimperti and Andreadis 2015), being particularly important for skeleton formation (reviewed in Marie et al. 2014).

Besides cancer (reviewed in Blaschuk and Devemy 2009, Niit et al. 2015, Chen et al. 2021), CDH11 has been implicated in several other diseases, such as rheumatoid arthritis (reviewed in Chang et al. 2010, Dou et al. 2013, Sfikakis et al. 2017, Senolt et al. 2019, Nygaard and Firestein 2020), fibrosis (reviewed in Agarwal 2014), cardiovascular diseases (reviewed in Boda-Heggemann et al. 2009, Huynh 2017, Du et al. 2021), and neuropsychiatric disorders (reviewed in Redies et al. 2012).
Identifier: R-HSA-9762293
Species: Homo sapiens
The CDH11 gene consists of 14 exons, which encode two splice isoforms. Both splicing isoforms are expressed in the heart, brain, placenta, lung and bone, but not in the kidney, skeletal muscle, pancreas and liver (Okazaki et al. 1994; Kawaguchi et al. 1999). Several transcription factors have been shown to directly regulate CDH11 gene transcription, including HOXC8 (Lei et al. 2005; Lei et al. 2006; Li et al. 2014), ILF3 (Zhang et al. 2017), ZEB2 (Nam et al. 2012; Nam et al. 2014), HEYL (Liu et al. 2020), FOXF1 (Black et al. 2018), and BHLHE22 (Ross et al. 2012), and the transcription of CDH11 has also been shown to be influenced by a number of growth factors and hormones, such as FGF2 (Strutz et al. 2002; James et al. 2008), TNF (Wu et al. 2013), TGFB1 (Schneider et al. 2012; Schulte et al. 2013; Hahn et al. 2016; Cheng et al. 2018; Ruan et al. 2019; Doolin et al. 2021; Wilson et al. 2022), TGFB2 (Wecker et al. 2013; Theodossiou et al. 2019), GNRH1 (Peng et al. 2015), PTH (Yao et al. 2014), dexamethasone (Lecanda et al. 2000), progesterone (Chen et al. 1999). CDH11 can also affect TGFB1 signaling, thereby possibly creating a feedback loop (Passanha et al. 2022). Expression of mouse Cdh11 in mouse osteoblast-like cell line (MC3T3-E1) is not affected by osteogenic hormones triiodothyronine (T3) and 1,25-dihydroxyvitamin D3 at either mRNA or protein levels (Leugmayr et al. 2000).
Identifier: R-HSA-1912422
Species: Homo sapiens
Compartment: nucleoplasm, cytosol, endoplasmic reticulum membrane, endoplasmic reticulum lumen, Golgi membrane, Golgi lumen, plasma membrane
In humans and other mammals the NOTCH gene family has four members, NOTCH1, NOTCH2, NOTCH3 and NOTCH4, encoded on four different chromosomes. Their transcription is developmentally regulated and tissue specific, but very little information exists on molecular mechanisms of transcriptional regulation. Translation of NOTCH mRNAs is negatively regulated by a number of recently discovered microRNAs (Li et al. 2009, Pang et al.2010, Ji et al. 2009, Kong et al. 2010, Marcet et al. 2011, Ghisi et al. 2011, Song et al. 2009, Hashimoto et al. 2010, Costa et al. 2009).

The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011).

In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling.

Set (3 results from a total of 3)

Identifier: R-ALL-444210
Compartment: extracellular region
Identifier: R-ALL-444074
Compartment: extracellular region
Identifier: R-ALL-2045079
Compartment: cytosol

Drug (1 results from a total of 1)

Identifier: R-ALL-9717987
Compartment: cytosol
Primary external reference: Guide to Pharmacology: minodronic acid: 3164
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