About this Research Topic
Small GTPases are a well-known family of low molecular weight GTP-hydrolysing enzymes which cycle between an inactive, GDP-bound state and an active, GTP-bound state. The small GTPases family includes many members, such as Ras, Rho, Rab, and Arf, which regulate key cellular processes such as proliferation, differentiation, motility, vesicle trafficking, and cell growth. Therefore, their proper functioning is crucial for cellular homeostasis, while their deregulation is associated with different pathologies and has, in many cases, been linked to tumorigenic processes. For example, mutations in Ras proteins, which regulate cell proliferation, differentiation and survival, are among the most common genetic alterations in human cancer and, to date, no drug that can directly inhibit their oncogenic function has been approved by the FDA. Another family of small GTPases, the Rab family, plays a central role in the regulation of membrane tethering and vesicle trafficking, and its dysregulation can lead to cancer metastasis.
Ras proteins localize primarily to the inner leaflet of plasma membrane (PM), where they are laterally segregated into transient nano-scale domains, called nanoclusters, which are essential for high-fidelity signal transmission by the Ras/MAPK cascade. Ras proteins can form multiple homo-oligomeric complexes within the nanoclusters: the dynamics of Ras nanocluster assembly and disassembly controls the MAPK signal output, and its dysregulation perturbs the Ras/MAPK cascade. In addition, the interaction of Ras with the PM is crucial for signal transduction, since the disruption of the Ras/PM interaction blocks Ras oncogenic activity. Therefore, the molecular mechanisms that regulate Ras nanoclustering and interaction with the PM are potential targets for developing anti-Ras therapies.
Rab GTPases regulate vesicular trafficking, autophagy and lysosomal degradation, and their dysregulation is implicated in tumorigenesis and cancer cell metastasis. However, Rab GTPases interact with several effector proteins in different cellular contexts and vesicular compartments, and their function can vary as either oncogene or tumor suppressor depending on the interaction and the cell-type.
The goal of this Research Topic is to address the unanswered questions around the molecular mechanisms behind the function of Ras and Rab GTPases and their dysregulation in cancer, in order to contribute to the basic understanding of tumorigenic processes, and to unravel potential new pharmacological targets and clinical applications.
Areas to be covered in this research topic may include, but are not limited to:
• Ras and Rab signalling, and their deregulation in different cancer types.
• Ras mutations: importance in cancer diagnosis, prognosis and treatment.
• Ras nanoclusters and oligomerization.
• K-Ras/Plasma membrane interactions: a tractable therapeutic target.
• Rab GTPases: function, regulation, and therapy opportunities.
• The role of Rab GTPases in tumorigenesis and cancer cell metastasis.
• Development of inhibitors that target dysfunctional small GTPases.
• Potential new pharmacological targets for small GTPases-driven cancers.
Keywords: small GTPases, Ras, Ras mutations, Rab, Cancer therapy
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