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1.
Nutrients ; 13(6)2021 May 31.
Article in English | MEDLINE | ID: mdl-34073024

ABSTRACT

L-carnitine (LC) supplementation improves cardiac function in hemodialysis (HD) patients. However, whether reducing LC supplementation affects carnitine kinetics and cardiac function in HD patients treated with LC remains unclear. Fifty-nine HD patients previously treated with intravenous LC 1000 mg per HD session (three times weekly) were allocated to three groups: LC injection three times weekly, once weekly, and placebo, and prospectively followed up for six months. Carnitine fractions were assessed by enzyme cycling methods. Plasma and red blood cell (RBC) acylcarnitines were profiled using tandem mass spectrometry. Cardiac function was evaluated using echocardiography and plasma B-type natriuretic peptide (BNP) levels. Reducing LC administration to once weekly significantly decreased plasma carnitine fractions and RBC-free carnitine levels during the study period, which were further decreased in the placebo group (p < 0.001). Plasma BNP levels were significantly elevated in the placebo group (p = 0.03). Furthermore, changes in RBC (C16 + C18:1)/C2 acylcarnitine ratio were positively correlated with changes in plasma BNP levels (ß = 0.389, p = 0.005). Reducing LC administration for six months significantly decreased both plasma and RBC carnitine levels, while the full termination of LC increased plasma BNP levels; however, it did not influence cardiac function in HD patients.


Subject(s)
Carnitine/blood , Carnitine/pharmacokinetics , Dietary Supplements , Heart Failure/prevention & control , Heart/drug effects , Kidney Failure, Chronic/therapy , Renal Dialysis/methods , Aged , Carnitine/administration & dosage , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Heart/physiopathology , Heart Failure/complications , Humans , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/complications , Male , Middle Aged , Prospective Studies , Single-Blind Method
2.
Kurume Med J ; 66(3): 153-160, 2021 Oct 06.
Article in English | MEDLINE | ID: mdl-32848104

ABSTRACT

BACKGROUND: Carnitine plays a pivotal role in energy synthesis through ß-oxidation in mitochondria. Serum and tissue levels of free carnitine are significantly decreased in dialysis patients, whereas acylcarnitine levels are increased. However, the precise kinetics and fate of carnitine fractions in chronic kidney disease (CKD) patients who are not on dialysis have not been clarified. This study aims to determine the kinetics of serum carnitine fractions in patients who were not on dialysis. METHODS: Seventy-five CKD patients not on dialysis were recruited in this study. Serum and urinary carnitine fraction levels were measured to evaluate the kinetics and regulation of serum carnitine fractions. Carnitine fractions were measured by the enzymatic cycling method. RESULTS: Total and free serum carnitine levels did not change with progression of CKD, whereas acylcarnitine levels and the acyl/free carnitine ratio significantly increased. Serum acylcarnitine levels were inversely associated with estimated glomerular filtration rate (r2 = 0.239, p < 0.001), but free carnitine levels were not. Serum free carnitine levels were positively associated with urinary free carnitine excretion (r2 = 0.214, p < 0.001), but serum acylcarnitine levels were not. Multiple stepwise regression analysis revealed that urinary free carnitine excretion and blood urea nitrogen were independent determinants of serum free carnitine and acylcarnitine levels, respectively. CONCLUSIONS: The present study demonstrated that serum acylcarnitine levels increased with renal dysfunction independent of urinary excretion levels. Serum free carnitine was not affected by renal function in CKD patients who were not on dialysis.


Subject(s)
Carnitine/blood , Kidney Failure, Chronic/physiopathology , Kidney/metabolism , Renal Insufficiency, Chronic/blood , Adult , Aged , Amino Acids , Carnitine/analogs & derivatives , Female , Glomerular Filtration Rate , Humans , Kinetics , Male , Middle Aged , Renal Insufficiency, Chronic/physiopathology , Urea/blood , Uric Acid/blood
3.
Ther Apher Dial ; 25(3): 304-313, 2021 Jun.
Article in English | MEDLINE | ID: mdl-32777142

ABSTRACT

Serum carnitine is decreased in hemodialysis patients, which induces muscle atrophy. Thus, we examined the different effects of l-carnitine and exercise on exercise activity and muscle status in hemodialysis patients. Twenty patients were divided into l-carnitine and cycle ergometer groups and were followed for 3 months. Muscle and fat mass, physical activities, and muscle status were evaluated by an impedance, physical function test, and magnetic resonance imaging, respectively. The l-carnitine significantly increased muscle mass (P = .023) and thigh circumference (P = .027), decreased fat mass (P = .007), and shortened chair stand-up time (P = .002) and 10-m walk test (P = .037). The fat fraction was improved by the l-carnitine (P = .047). Compared with the exercise group, l-carnitine improved the changes in 10-m walk test (P = .026), chair stand-up time (P = .014), and thigh circumference (P = .022). Baseline fibroblast growth factor-21 and myostatin levels predicted the l-carnitine-associated changes in exercise activities. l-carnitine, rather than exercise, improved physical activity and muscle status in hemodialysis patients.


Subject(s)
Carnitine/administration & dosage , Dietary Supplements , Exercise Test/methods , Exercise/physiology , Muscles/drug effects , Renal Dialysis , Carnitine/blood , Exercise Test/statistics & numerical data , Female , Humans , Japan , Magnetic Resonance Imaging/methods , Male , Middle Aged , Muscles/diagnostic imaging , Muscles/physiology , Prospective Studies
4.
Mol Genet Metab ; 122(4): 216-222, 2017 12.
Article in English | MEDLINE | ID: mdl-29054612

ABSTRACT

Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and catalyzes the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine. To date, only 31 genetically confirmed patients with a DHP deficiency have been reported and the clinical, biochemical and genetic spectrum of DHP deficient patients is, therefore, still largely unknown. Here, we show that 4 newly identified DHP deficient patients presented with strongly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in urine and a highly variable clinical presentation, ranging from asymptomatic to infantile spasm and reduced white matter and brain atrophy. Analysis of the DHP gene (DPYS) showed the presence of 8 variants including 4 novel/rare missense variants and one novel deletion. Functional analysis of recombinantly expressed DHP mutants carrying the p.M250I, p.H295R, p.Q334R, p.T418I and the p.R490H variant showed residual DHP activities of 2.0%, 9.8%, 9.7%, 64% and 0.3%, respectively. The crystal structure of human DHP indicated that all point mutations were likely to cause rearrangements of loops shaping the active site, primarily affecting substrate binding and stability of the enzyme. The observation that the identified mutations were more prevalent in East Asians and the Japanese population indicates that DHP deficiency may be more common than anticipated in these ethnic groups.


Subject(s)
Amidohydrolases/chemistry , Amidohydrolases/genetics , Asian People , Metabolism, Inborn Errors/diagnosis , Point Mutation , Amidohydrolases/metabolism , Brain/pathology , Catalytic Domain , Child , Child, Preschool , Crystallization , Female , Gene Frequency , Genetic Variation , Humans , Infant , Japan , Male , Models, Molecular , Mutation, Missense , Uracil/analogs & derivatives , Uracil/urine
5.
Lett Drug Des Discov ; 14(6): 737-742, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28670223

ABSTRACT

BACKGROUND: Depression is highly prevalent in uremic patients undergoing hemodialysis (HD). We previously found that low free-carnitine levels are associated with depression severity in male patients undergoing HD. However, whether L-carnitine supplementation improves the depression state in male patients undergoing HD remains unclear. METHODS: Sixteen male patients undergoing HD were orally administered 900 mg L-carnitine daily or intravenously administered 1000 mg L-carnitine immediately after undergoing HD for 3 months. The depression state and various types of carnitine levels were evaluated using the self-rating depression scale (SDS) and tandem mass spectrometry, respectively, at baseline and 3 months after treatment. RESULTS: L-carnitine supplementation significantly increased serum levels of free and other acylcarnitine types, associated with improved SDS scores in male patients undergoing HD. Univariate analysis revealed that low baseline butyryl- and isovaleryl-/2-methylbutyryl-carnitine levels were significantly correlated with SDS scores after treatment. Multiple regression analysis revealed that butyryl-carnitine levels were a sole independent predictor of SDS scores after treatment (r2 = 0.533). CONCLUSION: L-carnitine supplementation for 3 months improved the depression state in uremic male patients undergoing HD. Thus, low butyryl-carnitine levels may predict the clinical response to L-carnitine supplementation in male patients undergoing HD and who have mild depression.

6.
Psychol Rep ; 120(2): 305-318, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28558622

ABSTRACT

Cognitive models of social anxiety posit that there are several types of maladaptive beliefs responsible for persistent social anxiety. Although these beliefs are theoretically important, currently there is no validated measure of these beliefs in Japan. In the present study, we translated into Japanese a well-validated measure of these beliefs, the Self-Beliefs Related to Social Anxiety (SBSA) Scale. The psychometric properties of the scale were also examined in two nonclinical samples ( ns = 401 and 30). Using confirmatory factor analysis, the Japanese version of the SBSA was found to have a correlated three-factor structure that consisted of "conditional beliefs," "unconditional beliefs," and "high standard beliefs." In addition, the Japanese version of the SBSA and its subscales demonstrated good internal consistency reliability and test-retest reliability. The Japanese version of the SBSA also demonstrated good convergent and divergent validity. Future applications of the Japanese version of the SBSA are discussed.


Subject(s)
Anxiety/psychology , Phobia, Social/psychology , Self Concept , Adolescent , Adult , Fear/psychology , Female , Humans , Japan , Male , Middle Aged , Psychometrics , Reproducibility of Results , Translations , Young Adult
7.
Mol Genet Metab Rep ; 11: 2-5, 2017 Jun.
Article in English | MEDLINE | ID: mdl-30547004

ABSTRACT

Isovaleric acidemia (IVA) is an organic acid disease caused by a deficiency of isovaleryl-CoA dehydrogenase. Deficiency of this enzyme leads to accumulation of organic acids, such as isovalerylcarnitine and isovalerylglycine. The proposed IVA treatments include leucine restriction and l-carnitine and/or glycine supplementation, which convert isovaleric acid into non-toxic isovalerylcarnitine and isovalerylglycine, respectively. We examined the therapeutic response using the leucine load test and performed a 10-year follow-up in the patient. METHODS: We evaluated the patient with IVA beginning at 5 years of age, when he presented with a mild to intermediate metabolic phenotype. Ammonia, free carnitine, isovalerylcarnitine, and isovalerylglycine were analyzed in the urine and blood after a meal consisting of 1600 mg leucine with glycine alone (250 mg/kg/day), l-carnitine alone (100 mg/kg/day), or both glycine and l-carnitine for four days each. RESULTS: (Leucine load test) Three hours after the meal, serum ammonia levels increased most dramatically with glycine treatment alone, then with both in combination, and least with l-carnitine alone. Urinary isovalerylglycine levels increased 2-fold more with glycine supplementation than those following supplementation with both agents or with l-carnitine alone. Treatment with both agents resulted in a gradual increase in urinary acylcarnitine levels during the 6-h period following the leucine load, reaching concentrations comparable to those observed with l-carnitine alone. (Clinical course) After initiation of both glycine (200 mg/kg/day) and l-carnitine (100 mg/kg/day) supplementation at 5 years of age, doses were gradually reduced to 111.7 mg/kg/day and 55.8 mg/kg/day, respectively, at 15 years of age. His mind and body had developed without any sequelae. DISCUSSION: We concluded that l-carnitine conjugated isovaleric acid earlier than glycine. Additionally, during the 10-year follow-up period, the patient displayed no clinical deterioration.

8.
J Inherit Metab Dis ; 37(5): 801-12, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24526388

ABSTRACT

ß-ureidopropionase (ßUP) deficiency is an autosomal recessive disease characterized by N-carbamyl-ß-amino aciduria. To date, only 16 genetically confirmed patients with ßUP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese ßUP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant ßUP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (≤ 1.3 %). Conversely, ßUP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human ßUP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that ßUP deficiency is not as rare as generally considered and screening for ßUP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.


Subject(s)
Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/genetics , Amidohydrolases/deficiency , Brain Diseases/epidemiology , Brain Diseases/genetics , Movement Disorders/epidemiology , Movement Disorders/genetics , Mutation/genetics , Purine-Pyrimidine Metabolism, Inborn Errors/epidemiology , Purine-Pyrimidine Metabolism, Inborn Errors/genetics , Alleles , Amidohydrolases/chemistry , Amidohydrolases/genetics , Child , Child, Preschool , Female , Gene Frequency , HEK293 Cells , Humans , Infant , Infant, Newborn , Japan/epidemiology , Male , Models, Molecular , Mutation, Missense/genetics , Nervous System Diseases/etiology , Nervous System Diseases/genetics , Phenotype , Prevalence
9.
J Med Food ; 15(1): 96-9, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22082101

ABSTRACT

We performed a transient bilateral common carotid artery occlusion on rats and investigated whether feeding an aqueous extract of Mycoleptodonoides aitchisonii, an edible mushroom, affected metabolism of monoamines in the cerebral cortex, possibly protecting against ischemic damage. Seventeen days after the surgery, concentrations of the dopamine (DA) metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and of homovanillic acid (HVA) in the cerebral cortex of the M. aitchisonii-fed group (MV) were higher than in the control ischemia (CV) group. The turnover rate of DA, which was indicated by (DOPAC+HVA)/DA, for the CV group was significantly lower than for the MV group, and the MV group value was the same rate as the sham-operated group. These data indicate that M. aitchisonii affects the dopaminergic neuronal system following brain ischemia damage in the cerebral cortex.


Subject(s)
Biological Products/pharmacology , Brain Ischemia/drug therapy , Cerebral Cortex/drug effects , Dopamine/metabolism , Homovanillic Acid/metabolism , Ischemic Attack, Transient/drug therapy , Polyporales , Agaricales , Animals , Biological Products/therapeutic use , Brain Ischemia/etiology , Brain Ischemia/metabolism , Carotid Artery Injuries/complications , Cerebral Cortex/metabolism , Ischemic Attack, Transient/etiology , Ischemic Attack, Transient/metabolism , Male , Rats , Rats, Wistar
10.
Yakugaku Zasshi ; 130(4): 471-7, 2010 Apr.
Article in Japanese | MEDLINE | ID: mdl-20371988

ABSTRACT

To clarify the whole picture of epidermal growth factor (EGF) signaling pathway, we identified proteins from the EGF-stimulated A431 cells by anti-phospho-tyrosine antibody column chromatography. Over 150 proteins were detected including previously unidentified proteins as well as well-studied proteins. Among these proteins, we picked up four proteins that had not been known in EGF signaling pathway and analyzed their functions. We report the functions of these proteins in this article. 1) CFBP interacts with CD2AP family proteins and functions as a key component in downregulation of EGF receptor protein level following EGF stimulation. 2) Ymer is found to be phosphorylated and ubiquitinated upon EGF stimulation, and functions as a regulator for the downregulation and endocytosis of EGF receptor. 3) CLPABP binds to mitochondria-specific phospholipids, cardiolipin, through its PH domain, and its complex includes various proteins related to mRNA metabolism. 4) GAREM is associated with Grb2 and Shp2. Each association affects the ERK activity. Finally, we discuss the possibilities that these proteins can be used as a novel biomarker protein for cancer and other diseases.


Subject(s)
Adaptor Proteins, Signal Transducing/isolation & purification , Biomarkers , Carrier Proteins/isolation & purification , Drug Design , ErbB Receptors/physiology , GRB2 Adaptor Protein/isolation & purification , Intracellular Signaling Peptides and Proteins/isolation & purification , Phosphoproteins/isolation & purification , Proteomics/methods , Signal Transduction/physiology , Adaptor Proteins, Signal Transducing/physiology , Carrier Proteins/physiology , Chromatography , Down-Regulation , Endocytosis , GRB2 Adaptor Protein/physiology , Humans , Intracellular Signaling Peptides and Proteins/physiology , Lipid-Linked Proteins , Phosphoproteins/physiology , Signal Transduction/genetics
11.
J Biol Chem ; 284(30): 20206-14, 2009 Jul 24.
Article in English | MEDLINE | ID: mdl-19509291

ABSTRACT

Adaptor proteins for the various growth factor receptors play a crucial role in signal transduction through tyrosine phosphorylation. Several candidates for adaptor proteins with potential effects on the epidermal growth factor (EGF) receptor-mediated signaling pathway have been identified by recent phosphoproteomic studies. Here, we focus on a novel protein, GAREM (Grb2-associated and regulator of Erk/MAPK) as a downstream molecule of the EGF receptor. GAREM is phosphorylated at tyrosine 105 and 453 after EGF stimulation. Grb2 was identified as its binding partner, and the proline-rich motifs of GAREM are recognized by the N- and C-terminal SH3 domains of Grb2. In addition, the tyrosine phosphorylations of GAREM are necessary for its binding to Grb2. Because the amino acid sequence surrounding tyrosine 453 is similar to the immunoreceptor tyrosine-based inhibitory motif, Shp2, a positive regulator of Erk, binds to GAREM in this phosphorylation-dependent manner. Consequently, Erk activation in response to EGF stimulation is regulated by the expression of GAREM in COS-7 and HeLa cells, which occurs independent of the presence of other binding proteins, such as Gab1 and SOS, to the activated EGF receptor. Furthermore, the expression of GAREM has an effect on the transformation activity of cultured cells. Together, these findings suggest that GAREM plays a key role in the ligand-mediated signaling pathway of the EGF receptor and the tumorigenesis of cells.


Subject(s)
ErbB Receptors/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , GRB2 Adaptor Protein/metabolism , Amino Acid Motifs , Animals , Binding Sites , COS Cells , Chlorocebus aethiops , GRB2 Adaptor Protein/analysis , GRB2 Adaptor Protein/genetics , Gene Expression , HeLa Cells , Humans , Molecular Sequence Data , Phosphorylation , Proline/chemistry , Proline/metabolism , Protein Binding , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Tyrosine/metabolism , src Homology Domains
12.
Biochim Biophys Acta ; 1783(6): 1036-47, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18191643

ABSTRACT

We identified a new protein containing the pleckstrin homology (PH) domain through tyrosine phosphoproteomics using epidermal growth factor-stimulated cells. The tandem PH domains of this protein can bind to mitochondria-specific phospholipid, cardiolipin or its dehydro product, phosphatidic acid; therefore, we have designated this protein as cardiolipin and phosphatidic acid-binding protein (CLPABP). In this study, we show that CLPABP is localized on the tubulin network and the mitochondrial surface in the granular form along with other proteins and RNA. The affinity of CLPABP to mitochondria is elevated depending on the extent of tyrosine phosphorylation. The CLPABP complex contains various proteins related to cytoplasmic mRNA metabolism. The unique subcellular localization of CLPABP requires its PH domains and a multifunctional protein, SF2p32, as its binding protein. The CLPABP granule also contains the cytochrome c transcript, which may be mediated by the RNA-binding protein HuR. Immunofluorescence staining reveals that the CLPABP granule is colocalized with cytochrome c and various ribosomal proteins that are present in the CLPABP complex. Therefore, the CLPABP RNA-protein complex may play a role in transporting cytochrome c mRNA and its translated product to the mitochondria.


Subject(s)
Cardiolipins/metabolism , Carrier Proteins/metabolism , Mitochondria/metabolism , RNA/metabolism , Tyrosine/metabolism , Animals , Antigens, Surface/metabolism , Apoptosis , COS Cells , Cardiolipins/genetics , Carrier Proteins/genetics , Cells, Cultured , Chlorocebus aethiops , Cytochromes c/metabolism , Cytoplasmic Granules/metabolism , ELAV Proteins , ELAV-Like Protein 1 , Fluorescent Antibody Technique , Humans , Lipid-Linked Proteins , Mitochondrial Proteins/metabolism , Phosphatidic Acids/metabolism , Phosphorylation , RNA/genetics , RNA, Mitochondrial , RNA-Binding Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Ribosomal Proteins/metabolism , Transfection , Tubulin/metabolism
13.
J Biol Chem ; 281(39): 28919-31, 2006 Sep 29.
Article in English | MEDLINE | ID: mdl-16895919

ABSTRACT

To decipher the global network of the epidermal growth factor (EGF) receptor-mediated signaling pathway, a large scale proteomic analysis of tyrosine-phosphorylated proteins was conducted. Here, we focus on characterizing a novel protein, CFBP (CIN85/CD2AP family binding protein), identified in the study. CFBP was found to be phosphorylated at tyrosine 204 upon EGF stimulation, and the CIN85/CD2AP family was identified as a binding partner. A proline-rich motif of CFBP is recognized by one of the three Src-homology 3 domains of CIN85/CD2AP, and the affinity of the interaction is regulated by the tyrosine phosphorylation of CFBP. They co-localize in actinenriched structures, and overexpression of CFBP induced morphological changes with actin reorganization. Furthermore, CFBP accelerated the EGF receptor's down-regulation by facilitating the recruitment of Cbl to the CD2AP/CIN85 complex. Two spliced variants of CFBP lacking either exon 5 or 8 are also expressed, and the variant lacking exon 5 without the proline-rich motif lacks the ability to bind to the CIN85/CD2AP family. The CFBP protein seems to play a key role in the ligand-mediated internalization and down-regulation of the EGF receptor.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Carrier Proteins/physiology , Cytoskeletal Proteins/physiology , Phosphoproteins/physiology , Tyrosine/chemistry , Amino Acid Sequence , Animals , Base Sequence , COS Cells , Carrier Proteins/chemistry , Cell Line, Tumor , Chlorocebus aethiops , ErbB Receptors/metabolism , HeLa Cells , Humans , Molecular Sequence Data , Phosphoproteins/chemistry , Phosphorylation
14.
J Biol Chem ; 281(34): 24612-22, 2006 Aug 25.
Article in English | MEDLINE | ID: mdl-16803894

ABSTRACT

The ligand-mediated down-regulation of the growth factor receptors is preceded by the involvement of various other factors. In particular, a ubiquitin ligase, Cbl, plays a central role in this event. Several candidates that have potential effects on the negative control of the epidermal growth factor (EGF) receptor have now been identified by our recent studies in phospho-proteomics. Among these molecules, we focus on characterizing a novel protein, Ymer, which is a tyrosine-phosphorylated and ubiquitinated protein. Ymer is found to be phosphorylated at tyrosine 145 and 146 upon EGF stimulation, and lysine 129 of Ymer has been identified as a ubiquitination site. Ymer has two motifs interacting with the ubiquitin (MIU) domains that might function as a binding site for the ubiquitinated EGF receptor. Although Ymer and EGF receptors are associated in an EGF-dependent manner, their interaction is required not only for MIU domains but also for the tyrosine phosphorylation of Ymer. Phosphorylated Ymer is mainly located at the plasma membrane with EGF receptor and functions in its endocytosis and degradation. Furthermore, EGF-mediated secondary modifications of an activated-EGF receptor are inhibited by overexpressing Ymer in COS7 cells. Therefore, Ymer may have competitive effects on the activation of the EGF receptor. Our findings suggest that Ymer functions as a novel inhibitor for the down-regulation of the EGF receptor and plays a crucial role for regulating the amount of the EGF receptor on the cell surface membrane.


Subject(s)
ErbB Receptors/metabolism , Proteins/metabolism , Cell Line , Down-Regulation , ErbB Receptors/antagonists & inhibitors , Humans , Intracellular Signaling Peptides and Proteins , Ligands , Phosphorylation , Signal Transduction , Tyrosine , Ubiquitin/metabolism
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