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Cancer and Metastasis Reviews
Published in: Cancer and Metastasis Reviews 3/2019

01-09-2019 | Metastasis

Functional disparities within the TIMP family in cancer: hints from molecular divergence

Authors: Celina Eckfeld, Daniel Häußler, Benjamin Schoeps, Chris D. Hermann, Achim Krüger

Published in: Cancer and Metastasis Reviews | Issue 3/2019

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Abstract

The members of the tissue inhibitor of metalloproteinase (TIMP) family (TIMP-1, 2, 3, 4) are prominently appreciated as natural inhibitors of cancer-promoting metalloproteinases. However, clinical and recent functional studies indicate that some of them correlate with bad prognosis and contribute to the progression of cancer and metastasis, pointing towards mechanisms beyond inhibition of cancer-promoting proteases. Indeed, it is increasingly recognized that TIMPs are multi-functional proteins mediating a variety of cellular effects including direct cell signaling. Our aim was to provide comprehensive information towards a better appreciation and understanding of the biological heterogeneity and complexity of the TIMPs in cancer. Comparison of all four members revealed distinct cancer-associated expression patterns and distinct prognostic impact including a clear correlation of TIMP-1 with bad prognosis for almost all cancer types. For the first time, we present the interactomes of all TIMPs regarding overlapping and non-overlapping interaction partners. Interestingly, the overlap was maximal for metalloproteinases (e.g., matrix metalloproteinase 1, 2, 3, 9) and decreased for non-protease molecules, especially cell surface receptors (e.g., CD63, overlapping only for TIMP-1 and 4; IGF-1R unique for TIMP-2; VEGFR2 unique for TIMP-3). Finally, we attempted to identify and summarize experimental evidence for common and unique structural traits of the four TIMPs on the basis of amino acid sequence and protein folding, which account for functional disparities. Altogether, the four TIMPs have to be appreciated as molecules with commonalities, but, more importantly, functional disparities, which need to be investigated further in the future, since those determine their distinct roles in cancer and metastasis.
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Metadata
Title
Functional disparities within the TIMP family in cancer: hints from molecular divergence
Authors
Celina Eckfeld
Daniel Häußler
Benjamin Schoeps
Chris D. Hermann
Achim Krüger
Publication date
01-09-2019
Publisher
Springer US
Keyword
Metastasis
Published in
Cancer and Metastasis Reviews / Issue 3/2019
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI
https://doi.org/10.1007/s10555-019-09812-6

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