Abstract
Cells and tissues are continuously exposed to both chemical and physical stimuli and dynamically adapt and respond to this variety of external cues to ensure cellular homeostasis, regulated development and tissue-specific differentiation. Alterations of these pathways promote disease progression—a prominent example being cancer. Rho GTPases are key regulators of the remodeling of cytoskeleton and cell membranes and their coordination and integration with different biological processes, including cell polarization and motility, as well as other signaling networks such as growth signaling and proliferation. Apart from the control of GTP–GDP cycling, Rho GTPase activity is spatially and temporally regulated by post-translation modifications (PTMs) and their assembly onto specific protein complexes, which determine their controlled activity at distinct cellular compartments. Although Rho GTPases were traditionally conceived as targeted from the cytosol to the plasma membrane to exert their activity, recent research demonstrates that active pools of different Rho GTPases also localize to endomembranes and the nucleus. In this review, we discuss how PTM-driven modulation of Rho GTPases provides a versatile mechanism for their compartmentalization and functional regulation. Understanding how the subcellular sorting of active small GTPase pools occurs and what its functional significance is could reveal novel therapeutic opportunities.
Highlights
Cell motility is essential for tissue development and homeostasis in multicellular organisms, but its dysregulation plays a crucial role in pathological processes such as tumor invasion and metastasis
RhoB is palmitoylated at Cys 189 and 192 upstream of the CAAX box motif [108,109], and we reported the ability of Rac1 to incorporate a palmitic acid at Cys 178 [110]
Rho GTPases govern many essential processes, including cell adhesion, survival, cell cycle and migration, which underlie their contribution to disease and justifies their exploration as important therapeutic targets in cancer and other disorders— in relation to their regulatory activity on cytoskeletal dynamics and plasma membrane (PM) organization
Summary
Cell motility is essential for tissue development and homeostasis in multicellular organisms, but its dysregulation plays a crucial role in pathological processes such as tumor invasion and metastasis. Changes in the actin cytoskeleton modulate focal adhesion dynamics and cell contraction and the physical properties (i.e., rigidity, compliance) of the cell, including its nucleus Characterizing how these cellular systems function in an integrated manner is essential to understand cell migration. The architecture of the ECM determines TC metastatic success by imposing a physical barrier to the scape of TCs from the primary tumor site During this process, networks regulating cell morphology and size and parameters associated with the extracellular environment are integrated to determine TC aggressiveness and metastatic ability. We discuss recent advances in our understanding of the post-translational regulation and subcellular compartmentalization of RhoGTPases and their functional relevance for enabling cell morphology control required during cell migration through 3D microenvironments. A better understanding of the mechanisms underlying the crosstalk between mechanical stimuli and biochemical responses through specific subcellular compartmentalization of RhoGTPases could help us to identify novel therapeutic targets against cancer disease
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