Universität zu Köln

Gruetzmacher, Nina (2024). Regulation of mTOR signaling by amino acids and Rapamycin-FKBP complexes. PhD thesis, Universität zu Köln.

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Abstract

The mechanistic target of Rapamycin (mTOR) serves as the central regulator of cell growth and metabolism, operating through two distinct complexes, mTORC1 and mTORC2. Abnormal mTORC1 activity is a common feature in various diseases including cancer, metabolic disorders, neurodegenerative conditions, as well as ageing. Therefore, it is crucial to understand the regulatory mechanisms of mTORC1 activity. In this work, I focused on elucidating the regulation of mTORC1 by amino acids as well as the small compound Rapamycin in complex with FKBPs. Amino acids play a dominant role in the regulation of mTORC1 activity and recent discoveries revealed an amino acid sensing machinery centered around the Rag GTPases. Although mammalian cells express four different Rags, RRAGA-D, the Rag paralogs were considered functionally redundant until recently. Furthermore, Rapamycin, a naturally-occuring mTOR inhibitor, selectively targets mTORC1 by forming a tertiary complex with the small immunophilin FKBP12. However, potential mTOR-independent effects of Rapamycin prompted further investigation. In the context of my PhD work, I demonstrated that there are indeed functional differences between RagA and RagB as well as RagC and RagD. Whereas RagA/B determines the response to amino acid depletion, RagC/D determines substrate specificity downstream of mTORC1. Moreover, I showed that Rapamycin selectively inhibits mTORC1 and that all observed effects can be attributed to mTOR inhibition. My data indicate that Rapamycin-treatment minimally alters the interactome of FKBPs, confirming its specificity towards mTOR. Additionally, I discovered a novel FKBP-interacting protein called PRR14L which may function as a transcriptional regulator with implications in cancer and vesicle exocytosis. Collectively, my findings offer valuable insights into the regulation of mTORC1 by amino acids and the specificity of Rapamycin towards mTOR inhibition. A comprehensive understanding of mTOR regulation holds immense promise in advancing our knowledge about cellular physiology and provides a foundation for the development of innovative therapeutic strategies.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Gruetzmacher, Nina gruetzmacher.n@gmail.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-719221
Date:	2024
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language mTOR, signaling, amino acids, Rapamycin, FKBP English
Date of oral exam:	21 September 2023
Referee:	Name Academic Title Demetriades, Constantinos Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/71922