Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling

Abstract

Ras homolog enriched in brain (Rheb1 and Rheb2), small GTPases, play a crucial role in regulating neuronal activity and have gained attention for their implications in cancer development, particularly in breast cancer. This study delves into the intricate connection between the multifaceted functions of Rheb1 in neurons and cancer, with a specific focus on the mTOR pathway. It aims to elucidate Rheb1's involvement in pivotal cellular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses while acknowledging that Rheb2 has not been extensively studied. Despite the recognized associations, a comprehensive understanding of the intricate interplay between Rheb1 and Rheb2 and their roles in both nerve and cancer remains elusive. This review consolidates current knowledge regarding the impact of Rheb1 on cancer hallmarks and explores the potential of Rheb1 as a therapeutic target in cancer treatment. It emphasizes the necessity for a deeper comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes, underscoring the existing gaps in our understanding. Additionally, the review highlights the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. By shedding light on the complicated roles between Rheb1/Rheb2 and cancer, this study provides valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeutic strategies for treating cancer.

Keywords: Rheb1; Rheb1 inhibitors; Rheb2; cancer; hallmarks; mTOR; neurons.

Figure 1

Crystal Structure of Rheb1: (A) The crystal structures of Rheb1 bound with GDP (Inactive State) and (B) Rheb1 bound with GTP (Active State) were aligned. (C) Rheb1 protein, with a length of 184 amino acids, is represented with the approximate locations of the G-boxes 1–5 and CSVM (CAAX motif) [23]. (D) Rheb2 protein, with a length of 183 amino acids, is represented by the approximate locations of the G-boxes 1–5 and CHLM (CAAX motif) [23]. Crystal structures are from the Protein Data Bank (PDB ID: 1XTQ, 1XTS).

Figure 2

The Rheb1 and Rheb2-mTOR signaling pathways have been extensively studied, from yeast to humans. This pathway plays a pivotal role in the regulation of cell growth, neurons, proliferation, cell size, and cancer proliferation. Canonical pathway: translation and cell cycle progression via S6K and 4E-BP1 inhibit autophagy via Ulk and ATG proteins. Non-canonical: mTORC2 regulates the cytoskeleton. Abbreviations: G-protein-coupled receptors (GPCRs), Insulin-like growth factor 1 (IGF-1), Mechanistic Target of Rapamycin (mTOR), Phosphatidylinositol-3 kinase (PI3K), Phosphatidylinositol 4,5-bisphosphate (PIP2), Phosphatidylinositol 3,4,5-trisphosphate (PIP3), Rheb1 GTPase, TBC1D7, Tuberous Sclerosis Complex (TSC) complex.

Figure 3

An overview of the different biological activities mediated by Rheb1. Rheb1 is crucial for numerous biological processes in addition to the central nervous system. Function in the central nervous system includes neural stem cell differentiation, neuronal growth and energy, synapse function, axon guidance, and neuroprotection.

Figure 4

Hallmarks of cancer include sustained proliferation signals, cancer cell survival, migration, invasion, and metastasis, resisting cell death, angiogenesis, possible replication immortality, inflammation promotion of cancer, avoidance of immune destruction, genetic instability and mutations, and metabolic reprogramming. Seven of the cancer hallmarks originate from tumor cells themselves, while the rest are involved in the tumor microenvironment (TME). Abbreviations: Bcl-2: B-cell lymphoma 2; Bcl-XL: B-cell lymphoma-extra-large; FKBP38: FK506-binding protein 38; HIF1: Hypoxia-inducible factor 1; IRF7: Interferon regulatory factor 7; MYC: Myelocytomatosis oncogene; mTORC1: Mechanistic target of rapamycin complex 1; p27: Cyclin-dependent kinase inhibitor 1B (CDKN1B); p70S6 kinase: S6 kinase 1 (RPS6KB1); PKM2: Pyruvate kinase isozyme M2; RNF168: Ring finger protein 168; Rheb1: Ras homolog enriched in brain 1; 4EBP1: Eukaryotic translation initiation factor 4E-binding protein 1.

Figure 5

The structures of Rheb1 inhibitors: NR1, Lonafarnib, Tipifarnib, FTI-277.