Abstract
The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed cell death or apoptosis. Membrane trafficking mediated by Rab proteins is controlled by intracellular localization of Rab proteins, Rab-membrane interactions and GTP-activation processes. Aberrant expression of Rab proteins has been reported in multiple cancers such as lung, brain and breast malignancies. Mutations in Rab-coding genes and/or post-translational modifications in their protein products disrupt the cellular vesicle trafficking network modulating tumorigenic potential, cellular migration and metastatic behavior. Conversely, Rabs also act as tumor suppressive factors inducing apoptosis and inhibiting angiogenesis. Deconstructing the signaling mechanisms modulated by Rab proteins during apoptosis could unveil underlying molecular mechanisms that may be exploited therapeutically to selectively target malignant cells.
Highlights
Cancers originate through dysregulation of normal cellular processes that either promote the growth, proliferation or migration of cells and/or suppress anti-tumorigenic functions such as programmed cell death or apoptosis
This review provides an overview of Ras-associated binding (Rab) family members, insights into the regulation of apoptotic programs by Rabs and their role in human diseases associated with poor outcomes, such as Alzheimer’s and neoplastic diseases
Rab proteins constitute the largest family of the RAS superfamily of small GTPases with more than 60 members identified in humans [7,8]
Summary
Cancers originate through dysregulation of normal cellular processes that either promote the growth, proliferation or migration of cells and/or suppress anti-tumorigenic functions such as programmed cell death or apoptosis. Intracellular communication and interaction of proteins within cellular components is fundamental for cell viability. These processes are regulated through multiple coordinated signaling cascades, which are orchestrated by a variety of proteins, enzymes and cellular receptors. Among the multiple signaling pathways, the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K) pathway play key roles in promoting cell survival and inhibiting apoptosis [1]. Among the many small monomeric G proteins, Ras-associated binding (Rab) proteins are master regulators of vesicle trafficking and as such control a multitude of signaling cascades and biological processes [2]. Among the multiple Rabs discovered in humans known to regulate signaling pathways, many control cellular survival and apoptosis. This review provides an overview of Rab family members, insights into the regulation of apoptotic programs by Rabs and their role in human diseases associated with poor outcomes, such as Alzheimer’s and neoplastic diseases
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