MT1-MMP, a transmembrane protein, is first known to localize to the cell membrane [29]. Recently, the importance of its subcellular localization has been of increased interest [29]. Subcellular mapping of MT1-MMP in the Human Protein Atlas (http://www.proteinatlas.org/ENSG00000157227-MMP14/cell (accessed on June 2022)) revealed that this protease is largely localized to the cytosol and to the intermediate filaments of the cytoskeleton [30]. Markedly, apart from the accumulation of MT1-MMP on the cell surface, MT1-MMP also localizes to the cytoplasm, caveolae, Golgi apparatus, and nucleus [8,13,26,27].

The structure of MT1-MMP, in terms of sequence domains, serves a vital role in directing the protease to extracellular and intracellular compartments, allowing for variability in localization [31] (Figure 1 and Figure 2). The hemopexin-like and cytoplasmic tail domains are involved in trafficking MT1-MMP throughout cellular compartments to the cell membrane, as demonstrated in breast carcinoma MCF7 cells [32,33,34]. Both domains allow MT1-MMP to be internalized to certain regions and organelles within the cell, including the tubulin cytoskeleton and Rab4 positive vesicles in the pericentrosome [32,33,34]. The cytoplasmic tail of MT1-MMP possesses the ability to allocate the protease, through the use of an “up/down” switch, to the cell membrane for the execution of its role in migration and invasion, as shown in HT1080 cells and invasive cancer cells [32,35,36]. Along with the cytoplasmic tail, Urena et al. (1999) identified C-terminal valine as a crucial element of proper trafficking and development of MT1-MMP [37]. Mutations in the C-terminal valine (Val⁵⁸²) have resulted in inhibition of specific MT1-MMP processing [37,38]. Evidently, the structure and domains of MT1-MMP play an important role in translocating this protease to multiple intracellular locations [39].

For instance, MT1-MMP is able to internalize inside the cell (i.e., HT1080 fibrosarcoma cells and human endothelial cells) by the use of caveolae, comprised of a small fraction of the plasma membrane formed into a lipid-raft structure, or clathrin-coated pits, through endocytosis [12,32,35,36,40,41,42,43]. Caveolae serve several roles in endocytosis and signal transduction, and they recycle cell surface molecules [32,44]. Hence, caveolae play an important role in translocating MT1-MMP to invadopodia [45]. Studies show that MT1-MMP is initially internalized before relocating to invadopodia through caveolae-mediated endocytosis [45]. This is essential in ensuring a consistent flow of active MT1-MMP to the plasma membrane [46]. Additionally, Rozanov et al. (2004) revealed that when MT1-MMP lacks the C-terminal cytoplasmic tail, this mutant is aberrantly trapped and localized to the caveolae [32]. This localization results in reduced cell migration and tumorigenesis, characterizing the cytoplasmic tail peptide sequence as paramount in the effective release of MT1-MMP from lipid rafts and the transport of the enzyme to the necessary cell surface targets [32,40]. The containment and ineffective release of MT1-MMP from caveolae through the regulation of the cytoplasmic tail indicates one mechanism of regulating this protease [32].

Additionally, endocytosis of MT1-MMP through the use of clathrin and caveolae was recorded inside fibrosarcoma, breast, colon and hepatocellular carcinoma cells [12,47]. When the vital component of caveolae, caveolin-1, was silenced, MT1-MMP’s ability to degrade the extracellular matrix was interrupted in MDA-MB-231 cells [47,48,49]. Consequently, the interaction between the cytoplasmic domain of the protease and Src-mediated tyrosine residue 573 phosphorylation of caveolin-1 further supports the interaction between MT1-MMP and caveolae and the crucial role of caveolae in regulating intracellular trafficking of MT1-MMP and its activity [50].

Furthermore, MT1-MMP localizes to the Golgi apparatus at the perinuclear regions for vesicular transport, as observed in both PC3 and BPH-1 prostate cell lines [51]. An actin and microtubule modulatory protein, LIMK1, is involved in regulating the vesicular trafficking of MT1-MMP for surface localization [51]. Some studies found that LIMK1 serves an essential role in regulating Golgi vesicle transport between the endoplasmic reticulum and Golgi apparatus [51]. When LIMK1 is inhibited, the targeting of MT1-MMP to the plasma membrane is significantly reduced, signifying the role of LIMK1 in MT1-MMP vesicular transport to the cell membrane’s surface [51]. This protease is dependent on signal sequences to direct them to the Golgi or endoplasmic reticulum. Although this is the case, some studies suggest that MT1-MMP lacks efficient signal sequences to effectively direct all of MT1-MMP to cell membrane/secretion [12]. For this reason, splicing, an additional mechanism, may assist in targeting MMPs to subcellular compartments, offering additional regulation [12].

With the further examination of the localization of MT1-MMP inside the cell, MT1-MMP was also discovered to localize inside the nucleus [52]. Ip et al. (2007) examined MT1-MMP subcellular localization in hepatocellular carcinoma, focusing on the nuclear MT1-MMP [52]. When MT1-MMP was found in nuclei from clinical specimens, interestingly, it was correlated with poor survival due to aggressive tumor characteristics [52]. MT1-MMP has a presumed nuclear localization sequence (NLS), translocating the protease to the nucleus [12,53]. However, other MMPs without a NLS were found to translocate to the nucleus via an additional mechanism, e.g., latching onto nuclear-translocating proteins [54,55].