Rho GTPases are a family of small proteins that act as molecular switches within cells, regulating processes that dictate a cell’s shape, movement, and overall behavior. They do this by switching between active and inactive states. Widespread in mammals, with 23 identified genes in humans, they are remarkably conserved across species from yeast to humans.
How Rho GTPases Function
Rho GTPases operate as molecular switches by cycling between two distinct states: an active, “on” state where they are bound to Guanosine Triphosphate (GTP), and an inactive, “off” state where they are bound to Guanosine Diphosphate (GDP). This cycling is tightly regulated by specific proteins that control the binding and hydrolysis of these nucleotides.
Guanine nucleotide Exchange Factors (GEFs) are proteins that activate Rho GTPases. They achieve this by promoting the release of GDP from the Rho GTPase, allowing the more abundant GTP in the cell to bind and switch the Rho GTPase to its active conformation. This conformational change enables the Rho GTPase to interact with downstream effector proteins, initiating various signaling pathways within the cell.
Conversely, GTPase-Activating Proteins (GAPs) inactivate Rho GTPases. GAPs accelerate the hydrolysis of GTP into GDP, turning the Rho GTPase “off.” This hydrolysis causes a conformational change that prevents the Rho GTPase from interacting with its effector proteins, terminating the signal.
Guanine nucleotide Dissociation Inhibitors (GDIs) add another layer of regulation by keeping Rho GTPases in an inactive, soluble state within the cytosol. GDIs bind to the Rho GTPase, preventing GDP dissociation and inhibiting GTP hydrolysis, sequestering it from the cell membrane where it would normally be active. This dual inhibitory function prevents premature activation and helps shuttle Rho GTPases to different cellular compartments.
Their Diverse Cellular Roles
Rho GTPases orchestrate a wide array of fundamental cellular processes by regulating the organization of the actin cytoskeleton. They are involved in dynamic changes to cell shape. The precise control of actin filament assembly and disassembly allows cells to adopt different forms.
These proteins are also involved in cell migration. Rho GTPases, including RhoA, Rac1, and Cdc42, regulate the dynamics of the actin cytoskeleton to facilitate cell protrusion and adhesion. For instance, RhoA promotes the formation of stress fibers and focal adhesions, while Rac1 and Cdc42 contribute to the formation of lamellipodia and filopodia, which are membrane extensions that help cells move across surfaces. This coordinated action is crucial during processes like wound healing and immune responses.
Beyond movement, Rho GTPases are involved in cell adhesion. They help form and maintain structures like focal adhesions that anchor cells to the extracellular matrix. They also play a role in cell division, specifically during cytokinesis. The formation of the contractile ring that pinches the cell in two is regulated by Rho GTPases, and defects can lead to cells with multiple nuclei or incomplete division. Rho GTPases also influence gene expression, linking external signals to changes in the cell’s genetic program.
Rho GTPases and Disease
When the precise regulation of Rho GTPase activity goes awry, it can contribute to the development and progression of various human diseases. Their abnormal function is frequently observed in cancer, where dysregulation can promote tumor growth, invasion, and metastasis. For example, increased levels of specific Rho GTPases like RhoA, RhoB, RhoC, Rac1, and Cdc42, along with their associated proteins like ROCK, have been linked to advanced stages of tumors and metastasis, particularly in breast cancer.
Neurological disorders also show connections to Rho GTPase malfunction. Variants in genes encoding Rho GTPases or their interacting proteins are associated with neurodevelopmental disorders. These proteins are involved in processes like neuronal development and neuroregeneration, and their disruption can lead to developmental brain abnormalities.
Cardiovascular diseases can arise from problems with Rho GTPase signaling. These proteins are involved in the formation of blood vessels during development (vasculogenesis) and the sprouting of new vessels from existing ones (angiogenesis). They also help maintain the integrity of mature blood vessel barriers. For instance, aberrant function of Rho-associated kinase (ROCK), a downstream target of Rho GTPases, has been implicated in various vascular diseases.