| First Author | Sakr M | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 21 | Pages | 8113-8127 |
| PubMed ID | 29643184 | Mgi Jnum | J:263885 |
| Mgi Id | MGI:6192882 | Doi | 10.1074/jbc.RA117.001503 |
| Citation | Sakr M, et al. (2018) Tracking the Cartoon mouse phenotype: Hemopexin domain-dependent regulation of MT1-MMP pericellular collagenolytic activity. J Biol Chem 293(21):8113-8127 |
| abstractText | Following ENU mutagenesis, a phenodeviant line was generated, termed the "Cartoon mouse," that exhibits profound defects in growth and development. Cartoon mice harbor a single S466P point mutation in the MT1-MMP hemopexin domain, a 200-amino acid segment that is thought to play a critical role in regulating MT1-MMP collagenolytic activity. Herein, we demonstrate that the MT1-MMPS466P mutation replicates the phenotypic status of Mt1-mmp-null animals as well as the functional characteristics of MT1-MMP(-/-) cells. However, rather than a loss-of-function mutation acquired as a consequence of defects in MT1-MMP proteolytic activity, the S466P substitution generates a misfolded, temperature-sensitive mutant that is abnormally retained in the endoplasmic reticulum (ER). By contrast, the WT hemopexin domain does not play a required role in regulating MT1-MMP trafficking, as a hemopexin domain-deletion mutant is successfully mobilized to the cell surface and displays nearly normal collagenolytic activity. Alternatively, when MT1-MMPS466P-expressing cells are cultured at a permissive temperature of 25 degrees C that depresses misfolding, the mutant successfully traffics from the ER to the trans-Golgi network (ER --> trans-Golgi network), where it undergoes processing to its mature form, mobilizes to the cell surface, and expresses type I collagenolytic activity. Together, these analyses define the Cartoon mouse as an unexpected gain-of-abnormal function mutation, wherein the temperature-sensitive mutant phenocopies MT1-MMP(-/-) mice as a consequence of eliciting a specific ER --> trans-Golgi network trafficking defect. |
