Role of the mTOR signalling pathway in salivary gland development

• Published in: The FEBS journal Vol. 286; no. 18; pp. 3701 - 3717
• Main Authors: Sakai, Manabu, Fukumoto, Moe, Ikai, Kazuki, Ono Minagi, Hitomi, Inagaki, Shinobu, Kogo, Mikihiko, Sakai, Takayoshi
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.09.2019
• Subjects: AKT protein; Animals; Animals, Newborn; Body weight; Chromones - pharmacology; Culture; development; differentiation; Embryo, Mammalian; Embryonic Development - genetics; Enzyme inhibitors; Fuel consumption; Inhibitors; Initiation factor eIF-4E; Kinases; Mechanistic Target of Rapamycin Complex 1 - drug effects; Mechanistic Target of Rapamycin Complex 2 - drug effects; Mice; Morphogenesis; Morphogenesis - genetics; Morpholines - pharmacology; Neonates; Organ culture; Organ Culture Techniques; Phosphorylation; Phosphorylation - drug effects; Protein kinase; Proteins; Rapamycin; Ribosomal protein S6; Ribosomal protein S6 kinase; Salivary gland; Salivary glands; Salivary Glands - growth & development; Salivary Glands - metabolism; Signal transduction; Signal Transduction - drug effects; Signaling; Sirolimus - pharmacology; Submandibular Gland - growth & development; Submandibular Gland - metabolism; TOR protein; TOR Serine-Threonine Kinases - genetics; salivary gland; development; differentiation; organ culture
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.14937

Development of the salivary gland is characterized by extensive branching morphogenesis. Although various molecules have been implicated in salivary gland development, the role of the mammalian target of rapamycin (mTOR) signalling pathway, including both mTOR complexes 1 and 2 (mTORC1 and 2), in salivary gland development is unknown. Here, we examined protein expression levels related to the mTOR signalling pathway using an ex vivo submandibular salivary gland (SMG) organ culture. We showed that branching buds in the salivary glands were substantially decreased and phosphorylation of mTORC1 signalling pathway related proteins (mTOR, p70 ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E‐binding protein 1) was inhibited by rapamycin (an mTOR inhibitor). In addition, AKT, which is an upstream protein kinase of mTORC1 and is downstream of mTORC2, is inhibited by LY294002 (a phosphatidylinositol 3‐kinase inhibitor), but not by rapamycin. Moreover, rapamycin‐treated ICR neonatal mice exhibited a reduction in both body weight and salivary glands compared with vehicle‐treated neonatal mice. The present data indicate that the mTOR signalling pathway, including both mTORC1 and mTORC2, plays a critical role in salivary gland development both in ex vivo SMG organ culture and ICR neonatal mice in vivo. Development of the salivary gland is characterized by extensive branching morphogenesis. The role of the mammalian target of rapamycin (mTOR) signalling pathway, including both mTOR complexes 1 and 2, in salivary gland development is unknown. We demonstrate that the mTOR signalling pathway, including phosphorylated AKT (T308 and S473) and mTOR signalling pathway related proteins (p70 ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E‐binding protein 1), plays a critical role in salivary gland development both in ex vivo organ culture and in vivo neonatal mice.