Signaling by Small GTPases at Cell-Cell Junctions: Protein Interactions Building Control and Networks

Abstract

A number of interesting reports highlight the intricate network of signaling proteins that coordinate formation and maintenance of cell-cell contacts. We have much yet to learn about how the in vitro binding data is translated into protein association inside the cells and whether such interaction modulates the signaling properties of the protein. What emerges from recent studies is the importance to carefully consider small GTPase activation in the context of where its activation occurs, which upstream regulators are involved in the activation/inactivation cycle and the GTPase interacting partners that determine the intracellular niche and extent of signaling. Data discussed here unravel unparalleled cooperation and coordination of functions among GTPases and their regulators in supporting strong adhesion between cells.

Figure 1.

(A) Classical regulation of Rho GTPases. Rho small GTPases are mostly found in an inactive, GDP-bound form, and is transiently activated when bound to GTP. This cycle is tightly modulated by guanine nucleotide exchange factors (GEF), which facilitates replacement of GDP for GTP. GTPase inactivation is facilitated by guanine nucleotide activating protein (GAP), as the latter increases the intrinsic GTP hydrolysis of small GTPases. Inactivated GTPases may be removed from membranes and maintained in the cytoplasm by interaction with RhoGDI. (B) Different proteins are able to interact directly with active or inactive GTPases or both forms. On interaction, different functions and cellular outcomes may occur (see text for more details).

Figure 2.

Potential models via which GTPase signaling is modulated at cell–cell contacts. In model 1, Rho GTPases are maintained at cell–cell contacts via association with binding proteins in an inactive, GDP-bound form. On stimulation, the regulator of GTPases (GEF) is translocated to junctions to activate the small GTPase, enabling interaction with effector proteins. The process is reversed via recruitment of a GAP, which help with the hydrolysis of GTP into GDP, releasing phosphate (Pi). In model 2, it is predicted that inactivated Rho proteins are maintained at junctions in a complex with cytoskeletal proteins that may or may not interact with selected GEF or GAP (see also Fig. 3). Alternatively, GEF/GAP may interact with different partners at the membrane and be kept at close proximity to the Rho GTPase. On stimuli, transient activation/inactivation is achieved coordinately in a speedy manner. In both models, Rho GTPase activation may also occur by blocking locally the function of a GAP, enabling a shift to GTP-loaded GTPase (not shown for simplicity). See text and Tables 1 and 2 for more details and references. Diagrams are not drawn to scale.

Figure 3.

Examples of multiple interactions converging on specific proteins resident at junctions. Selected examples of the ability of a cytoskeletal protein or junctional protein to associate with different regulators is depicted here. Such association modulates the activation and localization of regulators (GEF and GAP) by controlling their recruitment or retention at junctions. Each regulator can then modulate the activity of a specific GTPase; shown here is the GTPase that is modified specifically at junctions on modulation of the partner. Ternary complexes among partners and more than one regulator at junctions has not yet been formally shown. Of note is that, in some examples, interactions between partners and regulators can also be found in the cytoplasm in addition to junctions. For more details and references, see text and Tables 1 and 2. Diagrams are not drawn to scale.