TIMP2 explained

Tissue inhibitor of metalloproteinases 2 (TIMP2) is a gene and a corresponding protein. The gene is a member of the TIMP gene family. The protein is thought to be a metastasis suppressor.

Function

The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases (MMP), a group of peptidases involved in degradation of the extracellular matrix. In addition to an inhibitory role against metalloproteinases, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix.^[1] TIMP2 functions as both an MMP inhibitor and an activator. TIMPs inhibit active MMPs, but different TIMPs inhibit different MMPs better than others. For example, TIMP-1 inhibits MMP-7, MMP-9, MMP-1 and MMP-3 better than TIMP-2, and TIMP-2 inhibits MMP-2 more effectively than other TIMPs.^[2]

In melanocytic cells TIMP2 gene expression may be regulated by MITF.^[3]

A recent discovery is that TIMP2 plays an important role in hippocampal function and cognitive function. It plays a critical role in the benefit conferred to old mice when given human umbilical cord blood.^{[4] [5]} Its role in hippocampal function was later described to be related to its interactions with the extracellular matrix to regulate neurogenesis and dendritic spines plasticity.^[6]

Interactions

TIMP2 has been shown to interact with:

• MMP14^[7] and
• MMP2.^{[8] [9] [10] [11]}

See also

• TIMP1, TIMP3, TIMP4

Further reading

• Liotta LA, Stetler-Stevenson W, Steeg PS . Metastasis suppressor genes . Important Advances in Oncology . 85–100 . 1991 . 1869284 .
• Stetler-Stevenson WG, Seo DW . TIMP-2: an endogenous inhibitor of angiogenesis . Trends in Molecular Medicine . 11 . 3 . 97–103 . March 2005 . 15760767 . 10.1016/j.molmed.2005.01.007 .

External links

• The MEROPS online database for peptidases and their inhibitors: I35.002

Notes and References

1. Web site: Entrez Gene: TIMP2 TIMP metallopeptidase inhibitor 2 .
2. Bourboulia D, Stetler-Stevenson WG . Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion . Seminars in Cancer Biology . 20 . 3 . 161–168 . June 2010 . 20470890 . 2941566 . 10.1016/j.semcancer.2010.05.002 .
3. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E . Novel MITF targets identified using a two-step DNA microarray strategy . Pigment Cell & Melanoma Research . 21 . 6 . 665–676 . December 2008 . 19067971 . 10.1111/j.1755-148X.2008.00505.x . 24698373 . free .
4. Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, Berdnik D, Shen JC, Zou B, Xie XS, Tingle M, Hinkson IV, Angst MS, Wyss-Coray T . Human umbilical cord plasma proteins revitalize hippocampal function in aged mice . Nature . 544 . 7651 . 488–492 . April 2017 . 28424512 . 5586222 . 10.1038/nature22067 . 2017Natur.544..488C .
5. Blood from human babies makes brains of elderly mice young again. New Scientist. Apr 29, 2017.
6. Ferreira AC, Hemmer BM, Philippi SM, Grau-Perales AB, Rosenstadt JL, Liu H, Zhu JD, Kareva T, Ahfeldt T, Varghese M, Hof PR, Castellano JM . Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity . Molecular Psychiatry . 28 . 9 . 3943–3954 . September 2023 . 37914840 . 10730400 . 10.1038/s41380-023-02296-5 .
7. Zucker S, Drews M, Conner C, Foda HD, DeClerck YA, Langley KE, Bahou WF, Docherty AJ, Cao J . Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP) . The Journal of Biological Chemistry . 273 . 2 . 1216–1222 . January 1998 . 9422789 . 10.1074/jbc.273.2.1216 . free .
8. Morgunova E, Tuuttila A, Bergmann U, Tryggvason K . Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2 . Proceedings of the National Academy of Sciences of the United States of America . 99 . 11 . 7414–7419 . May 2002 . 12032297 . 124245 . 10.1073/pnas.102185399 . free . 2002PNAS...99.7414M .
9. Overall CM, Tam E, McQuibban GA, Morrison C, Wallon UM, Bigg HF, King AE, Roberts CR . Domain interactions in the gelatinase A.TIMP-2.MT1-MMP activation complex. The ectodomain of the 44-kDa form of membrane type-1 matrix metalloproteinase does not modulate gelatinase A activation . The Journal of Biological Chemistry . 275 . 50 . 39497–39506 . December 2000 . 10991943 . 10.1074/jbc.M005932200 . free .
10. Bigg HF, Shi YE, Liu YE, Steffensen B, Overall CM . Specific, high affinity binding of tissue inhibitor of metalloproteinases-4 (TIMP-4) to the COOH-terminal hemopexin-like domain of human gelatinase A. TIMP-4 binds progelatinase A and the COOH-terminal domain in a similar manner to TIMP-2 . The Journal of Biological Chemistry . 272 . 24 . 15496–15500 . June 1997 . 9182583 . 10.1074/jbc.272.24.15496 . free .
11. Kai HS, Butler GS, Morrison CJ, King AE, Pelman GR, Overall CM . Utilization of a novel recombinant myoglobin fusion protein expression system to characterize the tissue inhibitor of metalloproteinase (TIMP)-4 and TIMP-2 C-terminal domain and tails by mutagenesis. The importance of acidic residues in binding the MMP-2 hemopexin C-domain . The Journal of Biological Chemistry . 277 . 50 . 48696–48707 . December 2002 . 12374789 . 10.1074/jbc.M209177200 . free .