Structure of melanoma inhibitory activity protein, a member of a recently identified family of secreted proteins

Lougheed, Julie C.; Holton, James M.; Alber, Tom; Bazán, J. Fernando; Handel, Tracy M.

doi:10.1073/pnas.091601698

Cited by 50 publications

(57 citation statements)

References 30 publications

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“…We have recently determined the three-dimensional structure of MIA by NMR (Stoll et al, 2001), and our data were subsequently confirmed by X-ray analysis (Lougheed et al, 2001). It was shown that MIA forms a small globular SH3 domain-like structure stabilized by two disulfide bonds.…”

Section: Bosserhoff Et Almentioning

confidence: 78%

Active Detachment Involves Inhibition of Cell-Matrix Contacts of Malignant Melanoma Cells by Secretion of Melanoma Inhibitory Activity

Bosserhoff

Stoll

Sleeman

et al. 2003

Laboratory Investigation

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SUMMARY:Melanoma inhibitory activity (MIA) has been identified as a small protein secreted from malignant melanoma cells.Recent results revealed a direct interaction of MIA and epitopes within extracellular matrix proteins including fibronectin. The aim of this study was to analyze functional consequences mediated by this interaction. Here we show that MIA interferes specifically with attachment of melanoma cells to fibronectin, a phenomenon we refer to as active detachment. Antibodies inhibiting binding of ␣4␤1 and ␣5␤1 integrins to fibronectin cross-react specifically with MIA, suggesting that MIA shares significant structural homology with the binding pockets of these integrins and thereby masks the respective epitopes on extracellular matrix molecules. Several peptides derived from fibronectin and from a phage display screening were tested with respect to a potential MIA-inhibitory effect. In vitro tests identified two peptides affecting MIA function; both inhibited growth of melanoma metastases in vivo. In summary, we conclude that MIA may play a role in tumor progression and spread of malignant melanomas via mediating active detachment of cells from extracellular matrix molecules within their local milieu. Further, our results suggest that inhibiting MIA functions in vivo may provide a novel therapeutic strategy for metastatic melanoma disease. (Lab Invest 2003, 83:1583-1594.

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Section: Bosserhoff Et Almentioning

confidence: 78%

Active Detachment Involves Inhibition of Cell-Matrix Contacts of Malignant Melanoma Cells by Secretion of Melanoma Inhibitory Activity

Bosserhoff

Stoll

Sleeman

et al. 2003

Laboratory Investigation

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“…cently identified by NMR and x-ray crystallography of MIA (6,9). The N terminus coding for the signal sequence is quite divergent, but analysis by Kyte-Doolittle blots revealed conservation of the hydrophobic character that is functionally important.…”

Section: Resultsmentioning

confidence: 99%

“…Additional in vivo studies revealed the importance of MIA for metastasis of malignant melanomas (7,8). Furthermore, we and others (6,9) have shown that MIA adopts an SH3 domain-like structure and interacts directly with fibronectin.…”

mentioning

confidence: 99%

Specific Expression and Regulation of the New Melanoma Inhibitory Activity-related Gene MIA2 in Hepatocytes

Bosserhoff¹,

Moser

Schölmerich

et al. 2003

Journal of Biological Chemistry

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The novel human gene MIA2 encoding a melanoma inhibitory activity (MIA) homologous protein was identified by a GenBank TM search. MIA2, together with MIA, OTOR, and TANGO, belongs to the novel MIA gene family sharing important structural features, significant homology at both the nucleotide and protein levels, and similar genomic organization. In situ hybridization, reverse transcriptase-PCR, and Northern blots presented a highly tissue-specific MIA2 expression pattern in the liver. Promoter studies analyzing transcriptional regulation of MIA2 revealed an HNF-1-binding site at position ؊236 controlling hepatocyte-specific expression. Mutation of the site led to a complete loss of promoter activity in HepG2 cell. Further sites detected in the MIA2 promoter were consensus binding sites for SMAD and STAT3, Consistently, stimulation of MIA2 mRNA expression occurred by treatment with interleukin-6, transforming growth factor-␤, and conditioned medium from activated hepatic stellate cells. In accordance with these results, MIA2 mRNA was found to be increased in liver tissue of patients with chronic hepatitis C infection compared with controls. MIA2 mRNA levels were significantly higher in patients with severe fibrosis or inflammation than in patients with less severe fibrosis or inflammation. In summary our data indicate that MIA2 represents a potential novel acute phase protein and MIA2 expression responds to liver damage. The increased transcription in more severe chronic liver disease suggests that MIA2 may serve as a marker of hepatic disease activity and severity.

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“…For a deeper insight into the functional properties of MIA, multidimensional NMR (Stoll et al, 2000(Stoll et al, , 2001 and X-ray crystallography (Lougheed et al, 2001) were used to solve the three-dimensional structure of MIA. The corresponding data indicate that MIA defines a novel type of secreted protein, which adopts an SH3 domain-like fold in solution.…”

Section: Introductionmentioning

confidence: 99%

Functional role of MIA in melanocytes and early development of melanoma

et al. 2004

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The protein MIA (melanoma inhibitory activity) is highly expressed in malignant melanomas but not in melanocytes. Furthermore, expression of MIA correlates with tumor progression in vivo. Here, MIA-dependent changes of gene expression after long-term inhibition of MIA expression in the human melanoma cell line HMB2 were investigated. Primarily, we observed characteristic changes in cell morphology, and also found re-established cell-cell contacts in MIA-deficient cell clones grown in monolayer culture. Real-time reverse transcription-polymerase chain reaction (RT-PCR) showed a downregulation of N-cadherin expression and a reinduction of E-cadherin expression in the MIA-deficient cell clones. Further, both cancer cDNA array and protein arrays verified a marked downregulation of several other melanoma-associated genes (e.g. membrane-type 1 matrix metalloproteinase tissue-type plasminogen activator integrin b3, secreted protein acidic and rich in cysteins and fibronectin) in the MIA-deficient melanoma cells, confirmed by real-time RT-PCR and Western blotting. As all these molecules are associated with migration, the effect of MIA on migration of human primary melanocytes was analysed. In the presence of MIA, we observed enhanced migratory ability of melanocytic cells, induction of melanoma-associated genes as well as inhibition of apoptosis due to anoikis. These results suggest that expression of MIA promotes melanoma progression by inducing further melanoma-associated genes.

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Structure of melanoma inhibitory activity protein, a member of a recently identified family of secreted proteins

Cited by 50 publications

References 30 publications

Active Detachment Involves Inhibition of Cell-Matrix Contacts of Malignant Melanoma Cells by Secretion of Melanoma Inhibitory Activity

Active Detachment Involves Inhibition of Cell-Matrix Contacts of Malignant Melanoma Cells by Secretion of Melanoma Inhibitory Activity

Specific Expression and Regulation of the New Melanoma Inhibitory Activity-related Gene MIA2 in Hepatocytes

Functional role of MIA in melanocytes and early development of melanoma

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