Abstract
The serine/threonine protein kinase mechanistic target of rapamycin (mTOR) has been implicated in the regulation of an array of cellular functions including protein and lipid synthesis, proliferation, cell size and survival. Here, we describe the role of mTOR during haemopoiesis within the context of mTORC1 and mTORC2, the distinct complexes in which it functions. The use of conditional transgenic mouse models specifically targeting individual mTOR signalling components, together with selective inhibitors, have generated a significant body of research emphasising the critical roles played by mTOR, and individual mTOR complexes, in haemopoietic lineage commitment and development. This review will describe the profound role of mTOR in embryogenesis and haemopoiesis, underscoring the importance of mTORC1 at the early stages of haemopoietic cell development, through modulation of stem cell potentiation and self-renewal, and erythroid and B cell lineage commitment. Furthermore, the relatively discrete role of mTORC2 in haemopoiesis will be explored during T cell development and B cell maturation. Collectively, this review aims to highlight the functional diversity of mTOR signalling and underline the importance of this pathway in haemopoiesis.
Highlights
Mechanistic target of rapamycin is a serine/threonine protein kinase which was initially identified due to its ability to be inhibited by rapamycin, an antifungal macrolide first characterised in Streptomyces hygroscopicus
The Mechanistic target of rapamycin (mTOR)-mediated signalling pathway mTOR is activated by a variety of upstream mediators including growth factor (GF) receptors, and nutrients such as glucose and amino acids (AAs). mTOR belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family and forms two distinct complexes — mTORC1 and mTORC2
Through mTORC1 and mTORC2, the mTOR signalling pathway plays a critical role in protein and lipid biosynthesis, cell survival, migration, cell development and cell cycling
Summary
Mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase which was initially identified due to its ability to be inhibited by rapamycin, an antifungal macrolide first characterised in Streptomyces hygroscopicus. MTOR belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family and forms two distinct complexes — mTORC1 and mTORC2. These complexes share the proteins mTOR, GβL, DEPTOR and Tti1/Tel. Rapamycin interacts with FK506-binding proteins, such as FKBP12, with high affinity and the resultant complex interacts with mTOR in the context of mTORC1 to allosterically inhibit mTORC1 activity [3,4]. TSC proteins form a heterodimer and inhibit Ras homolog enriched in brain (RHEB), a positive regulator of mTORC1, which binds to mTORC1 causing conformational changes in the protein and activation [5]
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