Page 17 - Molecular features of low-grade developmental brain tumours

GENERAL INTRODUCTION & OUTLINE OF THE THESIS
been seen in low grade gliomas including, GGs, DNTs and SEGAs (Figure 2). Similarly, to the ERK/MAPK pathway, the mTOR pathway is activated by growth factors, cytokines and hormones. As a member of the phosphatidylinositol 3-kinase related kinase (PIKK) family, mTOR functions as catalytic subunit of two distinct multi-protein complexes called mTORC1 and mTORC2, which have distinct molecular compositions 103. Specific to mTORC1 are regulatory-associated protein of mTOR (RAPTOR) and proline-rich AKT1 substrate 40 kDa (PRAS40), whereas mTORC2 contains rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinase-interacting protein 1 (mSIN1), and protein observed with RICTOR (PROTOR). Dysregulation of mTOR may affect proliferation and migration of neural progenitor cells, neuronal soma size, dendritogenesis and formation of dendritic spines, axon outgrowth, astrocyte proliferation and cortical lamination 103. The role of mTORC1 in neurodevelopment is well established. Via phosphoinositide-3′ kinase (PI3K) and phosphoinositide-dependent kinase-1 (PDK1), AKT is activated and can inhibit the TSC complex formed by hamartin (encoded by TSC1), tuberin (encoded by TSC2), together with TBC1 domain family member 7 (TBC1D7). This TSC complex functions as a GAP for small G-protein Ras homology enriched in brain (RHEB), acting as an upstream regulator of mTORC1 104-106. Downstream of mTORC1, the ribosomal protein S6 kinase beta-1 (S6K1)/S6 and eukaryotic initiation factor 4E-binding protein 1(4E-BP1)/ Eukaryotic translation initiation factor 4E (eIF4E) can initiate translation 107.
Loss of function mutations in TSC1 or TSC2 result in constitutive activation of the mTORC1 pathway 108. In TSC, germline mutations in TSC1 or TSC2 can be familial inherited in an autosomal dominant fashion, but more often are sporadic in nature. Approximately, 60% of patients have a TSC2 mutation, while 30% of patients have a TSC1 mutation 109. In 10-15% of TSC patients, a TSC mutation cannot be identified, suggesting a potential low- level somatic mosaicism 110. Interestingly, TSC2 mutations generally result in more severe clinical manifestations than TSC1 mutations in TSC111. Lesions in TSC are thought to be caused by biallelic inactivation of either TSC1 or TSC2, also known as loss of heterozygosity (LOH), reflecting mosaicism that originates from loss of the corresponding wild-type allele. However, second-hit mutations are not always detected in cortical tubers and SEGAs 70,112,113. Potentially, only a small number of cells within the tuber/SEGA have LOH in either TSC1 or TSC2, suggesting limitations in the detection of second-hit mutations in these lesions 70. Alternatively, the mono-allelic TSC mutation, perhaps together with a destructive non- autonomous phenotype of mutated cells is sufficient for tuber/SEGA development 70,114. Furthermore, other pathways might also be at play in the development of these lesions.
Interestingly, ERK/MAPK activation can result in downstream activation of mTORC1 by inhibiting the TSC complex, whereas mTORC1 inhibition can lead to ERK/MAPK activation in turn, indicating that these pathways are intrinsically linked 115-118. Moreover, it has been shown that both the mTORC1 and the ERK/MAPK pathway can be activated by the lysosomal Ragulator complex consisting of late endosomal/lysosomal adaptor, MAPK and mTOR activator 1–5 (LAMTOR1/p18, LAMTOR2/p14, LAMTOR3/MP1, LAMTOR4/C7orf59 and LAMTOR5/HBXIP) 119-122. Dysregulation of the ERK/MAPK and mTOR pathway has been
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