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HADHB  -  hydroxyacyl-CoA dehydrogenase/3-ketoacyl...

Homo sapiens

Synonyms: ECHB, MSTP029, MTPB, TP-BETA, TP-beta, ...
 
 
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Disease relevance of HADHB

  • Genomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency [1].
  • Previous studies established that 15d-Delta12,14-prostaglandin J2 (15d-PGJ2) selectively inhibits Prm3 activity and TPbeta expression through a peroxisome proliferator-activated receptor (PPAR)gamma mechanism without affecting Prm1 activity or TPalpha expression in human megakaryocytic erythroleukemia (HEL) 92.1.7 cells [2].
 

High impact information on HADHB

  • Whole genome homozygosity mapping with 262 SNP markers mapped the disease gene to chromosome 5 where candidate genes Hadha and Hadhb, encoding the mitochondria trifunctional protein (MTP) alpha- and beta-subunits, respectively, are located [3].
  • Direct sequencing revealed a normal alpha-subunit, but detected a nucleotide T-to-A transversion in exon 14 (c.1210T>A) of beta-subunit (Hadhb) which resulted in a missense mutation of methionine to lysine (M404K) [3].
  • Amino acids 335-344 of the TPbeta C-tail were determined to be essential for the interaction of Rab11 with this receptor domain [4].
  • Expression of wild-type and mutant forms of the small GTPases RhoA and Cdc42 potently inhibited endocytosis of TPbeta, further indicating a role for the dynamic regulation of the actin cytoskeleton in this pathway [5].
  • This suggests that endocytosis of TPbeta requires active remodeling of the actin cytoskeleton [5].
 

Biological context of HADHB

 

Anatomical context of HADHB

 

Associations of HADHB with chemical compounds

  • On the other hand, signaling by TP beta is unaffected by either NO or prostacyclin [8].
  • Moreover, atorvastatin significantly reduced IP-mediated crossdesensitization of signalling by TP alpha (IC(50) 10.4 microm), but not by TP beta [14].
  • The G(q)-coupled thromboxane A(2) receptor subtype, TPalpha, and G(i)-coupled TPbeta subtype have been shown in human platelets [9].
  • Finally, agonist activation of TPalpha, but not of TPbeta, resulted in stimulation of phospholipase C-mediated inositol phosphate production in cells cotransfected with Gh [12].
  • In the present study, we demonstrate that agents that depolymerize (latrunculin B and cytochalasin D) or stabilize (jasplakinolide) the actin cytoskeleton blocked agonist-induced endocytosis of the beta isoform of the thromboxane A(2) receptor (TPbeta) in HEK293 cells [5].
 

Regulatory relationships of HADHB

  • Stimulation of the TPbeta receptor triggered ARF6 activation which was completely inhibited by the RGS domain of GRK2 known to specifically bind and sequester Galpha(q) [15].
 

Other interactions of HADHB

  • Immunohistochemistry demonstrated enrichment of HADHB in renin-producing renal juxtaglomerular cells [10].
  • Human HADHA and HADHB genes encode the subunits of an enzyme complex, the trifunctional protein, involved in mitochondrial beta-oxidation of fatty acids [6].
  • TPbeta, but not TPalpha, expression is required for the inhibition of VEGF-induced migration and angiogenesis [16].
  • In the present report, we investigated the effect of ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) expression on the agonist-induced internalization of the thromboxane A(2) beta receptor (TPbeta receptor) [17].
  • Moreover, Galpha(s)-R201C, a constitutively active form of Galpha(s), had no effect on internalization of the TPbeta, CXCR4, and beta(2)-adrenergic receptors [17].
 

Analytical, diagnostic and therapeutic context of HADHB

  • Truncation and site-directed mutagenesis revealed that a YX(3)phi motif (where X is any residue and phi is a bulky hydrophobic residue) found in the proximal portion of the carboxyl-terminal tail of TPbeta was critical for tonic internalization but had no role in agonist-induced internalization [18].
  • Immortalized human non-pigmented ciliary epithelial (NPE) cells (ODM-2) were shown to express the mRNA for the prostanoid TPalpha but not the TPbeta receptor using reverse transcription-polymerase chain reaction (RT-PCR) [19].

References

  1. Genomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency. Orii, K.E., Aoyama, T., Wakui, K., Fukushima, Y., Miyajima, H., Yamaguchi, S., Orii, T., Kondo, N., Hashimoto, T. Hum. Mol. Genet. (1997) [Pubmed]
  2. Synthetic peroxisome proliferator-activated receptor gamma agonists rosiglitazone and troglitazone suppress transcription by promoter 3 of the human thromboxane A2 receptor gene in human erythroleukemia cells. Coyle, A.T., Kinsella, B.T. Biochem. Pharmacol. (2006) [Pubmed]
  3. ENU mutagenesis identifies mice with cardiac fibrosis and hepatic steatosis caused by a mutation in the mitochondrial trifunctional protein {beta}-subunit. Kao, H.J., Cheng, C.F., Chen, Y.H., Hung, S.I., Huang, C.C., Millington, D., Kikuchi, T., Wu, J.Y., Chen, Y.T. Hum. Mol. Genet. (2006) [Pubmed]
  4. The intracellular trafficking of the G protein-coupled receptor TPbeta depends on a direct interaction with Rab11. Hamelin, E., Thériault, C., Laroche, G., Parent, J.L. J. Biol. Chem. (2005) [Pubmed]
  5. Involvement of actin in agonist-induced endocytosis of the G protein-coupled receptor for thromboxane A2: overcoming of actin disruption by arrestin-3 but not arrestin-2. Laroche, G., Rochdi, M.D., Laporte, S.A., Parent, J.L. J. Biol. Chem. (2005) [Pubmed]
  6. Genes for the human mitochondrial trifunctional protein alpha- and beta-subunits are divergently transcribed from a common promoter region. Orii, K.E., Orii, K.O., Souri, M., Orii, T., Kondo, N., Hashimoto, T., Aoyama, T. J. Biol. Chem. (1999) [Pubmed]
  7. Fluorescence in situ hybridization mapping of the alpha and beta subunits (HADHA and HADHB) of human mitochondrial fatty acid beta-oxidation multienzyme complex to 2p23 and their evolution. Aoyama, T., Wakui, K., Orii, K.E., Hashimoto, T., Fukushima, Y. Cytogenet. Cell Genet. (1997) [Pubmed]
  8. The alpha, but not the beta, isoform of the human thromboxane A2 receptor is a target for nitric oxide-mediated desensitization. Independent modulation of Tp alpha signaling by nitric oxide and prostacyclin. Reid, H.M., Kinsella, B.T. J. Biol. Chem. (2003) [Pubmed]
  9. Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors. Paul, B.Z., Jin, J., Kunapuli, S.P. J. Biol. Chem. (1999) [Pubmed]
  10. HADHB, HuR, and CP1 bind to the distal 3'-untranslated region of human renin mRNA and differentially modulate renin expression. Adams, D.J., Beveridge, D.J., van der Weyden, L., Mangs, H., Leedman, P.J., Morris, B.J. J. Biol. Chem. (2003) [Pubmed]
  11. Nm23-H2 interacts with a G protein-coupled receptor to regulate its endocytosis through an Rac1-dependent mechanism. Rochdi, M.D., Laroche, G., Dupré, E., Giguère, P., Lebel, A., Watier, V., Hamelin, E., Lépine, M.C., Dupuis, G., Parent, J.L. J. Biol. Chem. (2004) [Pubmed]
  12. Differential signaling by the thromboxane receptor isoforms via the novel GTP-binding protein, Gh. Vezza, R., Habib, A., FitzGerald, G.A. J. Biol. Chem. (1999) [Pubmed]
  13. Rapid, agonist-dependent phosphorylation in vivo of human thromboxane receptor isoforms. Minimal involvement of protein kinase C. Habib, A., Vezza, R., Créminon, C., Maclouf, J., FitzGerald, G.A. J. Biol. Chem. (1997) [Pubmed]
  14. Effect of the statin atorvastatin on intracellular signalling by the prostacyclin receptor in vitro and in vivo. O'Meara, S.J., Kinsella, B.T. Br. J. Pharmacol. (2004) [Pubmed]
  15. ARF6 activation by Galpha(q) signaling: Galpha(q) forms molecular complexes with ARNO and ARF6. Gigu??re, P., Rochdi, M.D., Laroche, G., Dupr??, E., Whorton, M.R., Sunahara, R.K., Claing, A., Dupuis, G., Parent, J.L. Cell. Signal. (2006) [Pubmed]
  16. Thromboxane A2 receptor signaling inhibits vascular endothelial growth factor-induced endothelial cell differentiation and migration. Ashton, A.W., Ware, J.A. Circ. Res. (2004) [Pubmed]
  17. Galphaq-coupled receptor internalization specifically induced by Galphaq signaling. Regulation by EBP50. Rochdi, M.D., Parent, J.L. J. Biol. Chem. (2003) [Pubmed]
  18. Role of the differentially spliced carboxyl terminus in thromboxane A2 receptor trafficking: identification of a distinct motif for tonic internalization. Parent, J.L., Labrecque, P., Driss Rochdi, M., Benovic, J.L. J. Biol. Chem. (2001) [Pubmed]
  19. Pharmacological and molecular biological (RT-PCR) characterization of functional TP prostanoid receptors in immortalized human non-pigmented ciliary epithelial cells. Sharif, N.A., Senchyna, M., Xu, S.X. Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics. (2002) [Pubmed]
 
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