The roles of cellular Factor XIII-A in osteoblasts
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Notice bibliographique
Résumé
Transglutaminases (TG) enzymes are expressed in wide variety of tissues and found in different cellular compartments, where they participate in various biological functions ranging from tissue stabilization to cell signaling. We have shown previously that MC3T3-E1/C14 osteoblasts express both transglutaminase 2 and Factor XIII-A (FXIII-A), the latter one appearing to be active as a transglutaminase during osteoblast differentiation. While data exists on the roles of FXIII-A as an extracellular stabilizer of matrix molecules in blood clots, during wound healing and during bone formation in vitro, the potential cellular functions of FXIII-A are not well understood. This thesis focuses on investigating the role of FXIII-A in osteoblasts and reports two new potential functions for FXIII-A. First contribution shows that in osteoblast FXIII-A activity targets the detyrosinated tubulin (Glu-tubulin) and promotes the formation of a high 150 kDa Glu-tubulin which is more stable in osteoblasts than the monomer form. This crosslinked Glu-tubulin is also membrane associated and found on the cell surface of osteoblasts where its presence is linked to secretion and deposition of extracellular matrix during osteoblast differentiation. We show that only α-tubulin, which gives rise to Glu-tubulin, is a TG substrate in vitro activity assay. The data in this thesis also shows that previously observed FXIII-A patches represent a pool of FXIII-A in caveolae, which are specialized membrane invaginations that have long been implicated in vesicular transport and signal transduction. We show FXIII-A co-localizes with caveolin-1 on the inner leaflet of plasma membrane in differentiating osteoblasts. Despite the presence of FXIII-A, caveolae had no detectable TG activity suggesting that FXIII-A may have a non-crosslinking function in caveolae. An irreversible TG inhibitor, NC9, which is capable of also altering TG enzyme conformation, displaced FXIII-A from caveolae which is linked to increased c-Src activation and increased caveolin-1 phosphorylation and homo-oligomerization. This suggests that cellular FXIII-A in osteoblasts has a role on regulating c-Src signaling. In summary, results in this thesis suggest that FXIII-A has both crosslinking and non-catalytic functions which regulate extracellular matrix accumulation and signaling pathways in osteoblasts, respectively.
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| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,000 | 0,001 |
| Science ouverte | 0,003 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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