Cancer and Metastasis Reviews

, Volume 38, Issue 3, pp 469–481 | Cite as

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

  • Celina Eckfeld
  • Daniel Häußler
  • Benjamin Schoeps
  • Chris D. Hermann
  • Achim KrügerEmail author


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.


TIMP Cancer Metastasis Interactome Proteases 



Molecular graphics and analyses were performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, USA, with support from NIH P41-GM103311.

Funding information

This work was supported by grants to A.K. from the Deutsche Forschungsgemeinschaft, Bonn, Germany (KR2047/1-3, and KR2047/8-1), and the Wilhelm-Sander-Stiftung, Munich, Germany (2016.124.1).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10555_2019_9812_MOESM1_ESM.pdf (120 kb)
ESM 1 (PDF 120 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Celina Eckfeld
    • 1
  • Daniel Häußler
    • 1
  • Benjamin Schoeps
    • 1
  • Chris D. Hermann
    • 1
  • Achim Krüger
    • 1
    Email author
  1. 1.School of Medicine, Institutes of Molecular Immunology and Experimental OncologyTechnical University of MunichMunichGermany

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