학술논문
Unmasking the tumourigenic role of SIN1/MAPKAP1 in the mTOR complex 2.
Document Type
Academic Journal
Author
Ezine E; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), Paris, France.; Département de Dermatologie, Hôpital Saint Louis, AP-HP, Paris, France.; Lebbe C; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), Paris, France.; Département de Dermatologie, Hôpital Saint Louis, AP-HP, Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), Paris, France.; Dumaz N; INSERM, U976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), Paris, France.; Université Paris Cité, Institut de Recherche Saint Louis (IRSL), Paris, France.
Source
Publisher: Wiley Country of Publication: United States NLM ID: 101597971 Publication Model: Print Cited Medium: Internet ISSN: 2001-1326 (Electronic) Linking ISSN: 20011326 NLM ISO Abbreviation: Clin Transl Med Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Although the PI3K/AKT/mTOR pathway is one of the most altered pathways in human tumours, therapies targeting this pathway have shown numerous adverse effects due to positive feedback paradoxically activating upstream signaling nodes. The somewhat limited clinical efficacy of these inhibitors calls for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer.
Main Body: Recent studies have shown the central role of mTOR complex 2 (mTORC2) as a pro-tumourigenic factor of the PI3K/AKT/mTOR pathway in a number of cancers. SIN1/MAPKAP1 is a major partner of mTORC2, acting as a scaffold and responsible for the substrate specificity of the mTOR catalytic subunit. Its overexpression promotes the proliferation, invasion and metastasis of certain cancers whereas its inhibition decreases tumour growth in vitro and in vivo. It is also involved in epithelial-mesenchymal transition, stress response and lipogenesis. Moreover, the numerous interactions of SIN1 inside or outside mTORC2 connect it with other signaling pathways, which are often disrupted in human tumours such as Hippo, WNT, Notch and MAPK.
Conclusion: Therefore, SIN1's fundamental characteristics and numerous connexions with oncogenic pathways make it a particularly interesting therapeutic target. This review is an opportunity to highlight the tumourigenic role of SIN1 across many solid cancers and demonstrates the importance of targeting SIN1 with a specific therapy.
(© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Main Body: Recent studies have shown the central role of mTOR complex 2 (mTORC2) as a pro-tumourigenic factor of the PI3K/AKT/mTOR pathway in a number of cancers. SIN1/MAPKAP1 is a major partner of mTORC2, acting as a scaffold and responsible for the substrate specificity of the mTOR catalytic subunit. Its overexpression promotes the proliferation, invasion and metastasis of certain cancers whereas its inhibition decreases tumour growth in vitro and in vivo. It is also involved in epithelial-mesenchymal transition, stress response and lipogenesis. Moreover, the numerous interactions of SIN1 inside or outside mTORC2 connect it with other signaling pathways, which are often disrupted in human tumours such as Hippo, WNT, Notch and MAPK.
Conclusion: Therefore, SIN1's fundamental characteristics and numerous connexions with oncogenic pathways make it a particularly interesting therapeutic target. This review is an opportunity to highlight the tumourigenic role of SIN1 across many solid cancers and demonstrates the importance of targeting SIN1 with a specific therapy.
(© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)