Disease relevance of ADD2

• Mutations in alpha- and beta-adducin are associated with hypertension [1].

High impact information on ADD2

• A striking divergence between alpha and beta mRNAs was noted in reticulocytes, where alpha adducin mRNA is present in at least 20-fold higher levels than that of beta adducin [2].
• Pleiotrophin regulates serine phosphorylation and the cellular distribution of beta-adducin through activation of protein kinase C [3].
• Furthermore, we demonstrate that PTN stimulates the degradation of beta-adducin in PTN-stimulated cells [3].
• We also demonstrate that PTN stimulates translocation of phosphoserine 713 and 726 beta-adducin either to nuclei, where it associates with nuclear chromatin and with centrioles of dividing cells, or to a membrane-associated site, depending on the phase of cell growth [3].
• Calmodulin-binding was inhibited by phosphorylation of beta-adducin and of a MARCKS-related domain peptide by PKA and PKC [4].

Chemical compound and disease context of ADD2

• In all women (N = 944), beta-adducin T allele carriers had a higher risk of hypertension than CC homozygotes (RR 1.81, CI 1.18-2.77, P = 0.007), but similar PRA and 24-hour urinary aldosterone excretion (P> 0.29) [5].

Biological context of ADD2

• Expression of adducin genes during erythropoiesis: a novel erythroid promoter for ADD2 [6].
• The very high levels of expression of ADD2 suggest that its promoter may be useful for directing erythroid-specific gene expression [6].
• Adducin is a heterodimeric cytoskeleton protein, the three subunits of which are encoded by genes (ADD1, ADD2, and ADD3) that map to three different chromosomes [7].
• In the European Project on Genes in Hypertension, we investigated whether polymorphisms in the genes encoding alpha-adducin (Gly460Trp), beta-adducin (C1797T) and gamma-adducin (A386G), alone or in combination, affected pulse pressure (PP), an index of vascular stiffness [1].
• Alternatively spliced exons in the 3' region are described and contain distinct coding regions, stop codons, and 3'UTR, corresponding to previously published beta-adducin cDNA sequences beta-1 and beta-2 [8].

Anatomical context of ADD2

• The early expression of ADD3 suggests that it may have a role in erythroblasts but is replaced by ADD2 in later stages of erythropoiesis [6].
• Using similar methods, beta-adducin (an Mr approximately 110,000 protein that forms a dimeric complex with alpha-adducin in the erythrocyte) is not present in fibroblasts [9].
• Adducin expression in cutaneous and oral lesions: alpha- and beta-adducin transcripts down-regulate with keratinocyte differentiation in stratified epithelia [10].
• A novel isoform of beta-adducin has been amplified and characterized from a human bone marrow cDNA library (GenBank #U43959) [11].
• PCR analysis indicates that this new beta-adducin isoform is expressed in fetal brain and liver, bone marrow, and NT-2 (neuroepithelial) cells, but is not detected in several other tissues [11].

Associations of ADD2 with chemical compounds

• Injection of fragments of Rabphilin-3A indicate that at least two distinct regions of the protein inhibit neurotransmitter release: the NH2-terminal region that binds Rab3A and is phosphorylated by protein kinases and the two C2 domains that interact with calcium, phospholipid, and beta-adducin [12].
• These results indicate that Rabphilin-3A binds to beta-adducin in the presence of Ca2+ and phosphatidylserine [13].
• We now demonstrate that PTN stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (PK) C substrate domain of beta-adducin through activation of either PKC alpha or beta [3].

Regulatory relationships of ADD2

• Expression of ADD2 was induced to very high levels (100 times baseline) in erythropoietin-stimulated cultures [6].

Other interactions of ADD2

• Polymorphisms in the ADD2 and ADD3 genes taken alone were not associated with these variables [14].
• ADD2 beta1 and beta4 variants show the same pattern of distribution with the highest expression in brain, fetal liver, and kidney [15].
• The myristoylated alanine-rich protein kinase C substrate-related domain of beta-adducin was identified as the dominant Ca2+-dependent calmodulin-binding site [4].
• AIM: To determine whether four potential genetic factors (polymorphisms in genes for alpha-adducin, beta-adducin, the G-protein beta-3 subunit and nitric oxide synthase) are important for the development of essential hypertension (EH) in Slovenian children and young adults with EH [16].
• Defects in stomatin, alpha-adducin, and beta-adducin have been implicated in erythrocyte disorders of cation permeability [17].

Analytical, diagnostic and therapeutic context of ADD2

• Assignment of the human beta-adducin gene (ADD2) to 2p13-p14 by in situ hybridization [18].

References