Disease relevance of Adam12

• Role of meltrin {alpha} (ADAM12) in obesity induced by high- fat diet [1].
• Compared with wild-type mice, meltrin alpha(-/-) mice displayed moderate resistance to weight gain induced by a high-fat diet, mainly because of an impaired increase in the number of adipocytes [1].
• However, overexpression of ADAM12 had no significant effect on overall health, as evidenced by body weight, and did not improve muscle pathology [2].
• ADAM12 overexpression does not improve outcome in mice with laminin alpha2-deficient muscular dystrophy [2].
• Furthermore, we show that ADAM12, a disintegrin and metalloprotease up-regulated in human breast cancer, accelerates tumor progression in a mouse breast cancer model [3].
• We observed loss of skeletal muscle and accelerated fibrosis and adipogenesis in 1-year-old mdx mice transgenically overexpressing ADAM12 (ADAM12(+)/mdx mice), even though their utrophin levels were mildly elevated compared with age-matched controls [4].

High impact information on Adam12

• KB-R7785 bound directly to ADAM12, suggesting that inhibition of ADAM12 blocked the shedding of HB-EGF [5].
• Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy [5].
• Meltrin-alpha, a member of the metalloproteinase/disintegrin protein family, appears to be required for myotube formation [6].
• More specifically ADAM12 appeared to prevent muscle cell necrosis in the mdx mice as evidenced by morphological analysis and by the reduced levels of serum creatine kinase [7].
• Role of metalloprotease disintegrin ADAM12 in determination of quiescent reserve cells during myogenic differentiation in vitro [8].

Biological context of Adam12

• To determine whether the proline-rich sequences interact with SH3 domains in several proteins, binding of recombinant SH3 domains to the meltrin alpha cytoplasmic domain was analysed by pull-down assays [9].
• These results may imply that meltrin alpha cytoplasmic domain is involved in a signal transduction for some biological function through the interaction with SH3-containing proteins [9].
• To delineate the functions of meltrin alpha and beta, we examined the expression patterns of their transcripts during embryogenesis [10].
• We also show that the region extending from the disintegrin to the transmembrane domain of ADAM12 and containing cell adhesion activity as well as the cytoplasmic domain of ADAM12 are required for ADAM12-mediated cell cycle arrest, while the metalloprotease domain is not essential [8].
• Meltrin alpha (ADAM12) is a metalloprotease-disintegrin whose specific expression patterns during development suggest that it is involved in myogenesis and the development of other organs [11].

Anatomical context of Adam12

• In this study we examined the role of the transmembrane ADAM12, a disintegrin and metalloprotease, which is normally associated with development and regeneration of skeletal muscle [12].
• Collectively, these results suggest that meltrin alpha and meltrin beta may play a role in osteoblast differentiation and/or function but are not likely to be involved in osteoclast fusion [13].
• Treatment of primary osteoblasts with 10 nM calcitriol increased meltrin beta expression more than 3-fold, and both meltrin alpha and meltrin beta expression is apparently regulated in a differentiation-associated manner in a mouse osteoblastic cell line, MC3T3E1 [13].
• The C-terminal Tyr901 of meltrin alpha was phosphorylated both in vitro and in cultured cells by v-Src [9].
• Although the meltrin alpha and beta transcripts exhibit distinct expression patterns during embryogenesis, both genes are mainly activated in mesenchymal cells that are derived from both mesoderm and ectoderm [10].

Associations of Adam12 with chemical compounds

• ADAM12 inhibited cell migration mediated by the alpha4beta1 but not the alpha5beta1 integrin [14].
• These results suggested that Hcy induced ADAM-12 [15].
• We show here that meltrin alpha was constitutively expressed in both undifferentiated and differentiated C2 skeletal muscle cells and also in fibroblasts [16].
• Replacement of Leu(73) in the putative alpha-helical region in the prodomain with proline resulted in retention of ADAM12 in the ER and a complete lack of its processing [17].
• In this paper, we show that the cytoplasmic tail of ADAM 12 mediates interactions with the non-receptor protein tyrosine kinase Src [18].

Physical interactions of Adam12

• Metalloprotease-disintegrin ADAM 12 binds to the SH3 domain of Src and activates Src tyrosine kinase in C2C12 cells [18].

Co-localisations of Adam12

• In Src-transformed cells, ADAM12 co-localized with Fish in podosomes [19].

Other interactions of Adam12

• In the present study, we tested the effect of overexpressing ADAM12 in dy(W) laminin-deficient mice. dy mice have a very severe clinical phenotype and would be expected to benefit greatly from enhanced regeneration [2].
• We have recently shown that overexpression of ADAM12 results in increased muscle regeneration and significantly reduced pathology in mdx, dystrophin deficient mice [2].
• The extracellular domain of the mature form of ADAM12 consists of the metalloprotease, disintegrin, cysteine-rich, and epidermal growth factor (EGF)-like domains [20].
• Using in situ RT-PCR, we have determined that murine mononuclear alveolar macrophages cultured under basal conditions express the transcript for meltrin-beta, but not for meltrin-alpha [21].
• Meltrin alpha (ADAM12) is a member of the ADAM (MDC) protein family characterized by the presence of metalloprotease and disintegrin domains [16].

Analytical, diagnostic and therapeutic context of Adam12

• To determine the roles Meltrin alpha plays in vivo, we generated Meltrin alpha-deficient mice by gene targeting [11].
• Upregulation of meltrin-alpha protein expression during cell fusion in alveolar macrophages and expression in osteoblastic cell lines were confirmed by Western blot analysis [21].
• Similarly, meltrin-alpha antisense oligonucleotides inhibited by 70% the formation of multinucleated osteoclast-like cells expressing tartrate-resistant acid phosphatase (TRAP) in co-cultures of bone marrow cells and osteoblastic cells (2107) in the presence of 1,25(OH)2D3 [21].
• However, meltrin-alpha mRNA appeared in mononuclear cells before cell fusion after treatment with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], a potent inducer of giant cell and osteoclast formation [21].
• Since endogenous meltrin alpha cannot be detected by immunofluorescence microscopy, we examined the location of the exogenously expressed protein by transfection [16].

References