Trends in Cell Biology
Volume 26, Issue 4, April 2016, Pages 241-248
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Opinion
Cdc42 and Cellular Polarity: Emerging Roles at the Golgi

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Cdc42 exists and functions at the plasma membrane and at the Golgi.

Cdc42 can replenish the pool at the plasma membrane via transport from the Golgi to the plasma membrane, which can occur either directly or indirectly by additional transit through the recycling endosome.

Cdc42 can act distinctly from the pool at the plasma membrane. A major way involves Cdc42 regulating bidirectional Golgi transport, acting to prevent retrograde cargoes from being sorted into coat protein I (COPI) vesicles and also promoting the formation of COPI tubules that act in anterograde Golgi transport.

Cdc42 can act in conjunction with the pool at the plasma membrane. One example is Cdc42 regulating the positioning of the Golgi complex. By coordinating this role with Cdc42 acting at the plasma membrane, surface protrusions are generated at the leading edge of migrating cells.

Cdc42 belongs to the Rho family of small GTPases and plays key roles in cellular events of polarity. This role of Cdc42 has typically been attributed to its function at the plasma membrane. However, Cdc42 also exists at the Golgi complex. Here we summarize major insights that have been gathered in studying the Golgi pool of Cdc42 and propose that Golgi-localized Cdc42 enables the cell to diversify the function of Cdc42, which in some cases represents new roles and in other cases acts to complement the established roles of Cdc42 at the plasma membrane. Studies on how Cdc42 acts at the Golgi also suggest key questions to address in the future.

Section snippets

Cdc42 Acts Not Only at the Plasma Membrane But Also at the Golgi

Small GTPases play integral roles in intracellular signal transduction pathways. Thus, they are involved in the regulation of virtually all cellular processes 1, 2, 3, 4. Small GTPases typically act as molecular switches, cycling between the active (GTP bound) and the inactive (GDP bound) state. In their active state, these GTPases are typically localized to cellular membranes. Thus, a current concept has been that the compartmentalization of signaling molecules through membrane localization

The Golgi Pool Acts as a Reservoir for the Plasma Membrane Pool

The possibility that the Golgi pool of Cdc42 could serve as a reservoir for the pool at the plasma membrane was initially suggested by a yeast study that sought to examine how Cdc42 acts in polarity in the absence of external cues [12]. In this study, the targeted delivery of Cdc42 to a localized region of the plasma membrane was found to require the actin cytoskeleton and also a myosin motor [12]. Delivery of Cdc42 was also found to be dependent on the exocyst [12], which is a multimeric

The Golgi Pool Acts Independently of the Plasma Membrane Pool

The Golgi pool of Cdc42 can also act independently of its pool at the plasma membrane. In mammalian cells, the Golgi is formed by a series of flattened cisternae that can be subdivided into the cis, medial, and trans regions [18]. Early studies had suggested that transport within the Golgi stacks occurs through vesicles formed by the coat protein I (COPI) complex [19]. Subsequently, intra-Golgi transport was found to be more complex, with the movement of the Golgi stacks mediating anterograde

The Golgi Pool Acts in Conjunction with the Plasma Membrane Pool

Golgi-localized Cdc42 can also act by coordinating its function with the pool at the plasma membrane for complex events of cellular polarity. One such role involves Cdc42 controlling the positioning of the Golgi. In directed cell migration, it is well known that the Golgi polarizes toward the direction of cell movement and that altering this polarization impairs cell migration 27, 28. This role of Cdc42 has been found to be dependent on microtubules and also under the control of ARHGAP21, a

Concluding Remarks

We have highlighted above three general ways that the Golgi pool of Cdc42 can act (summarized in Figure 1). It appears that the Golgi-localized Cdc42 enables the cell to diversify the function of this small GTPase, which in some cases represents new roles and in other cases acts to complement its established roles at the plasma membrane. The elucidation of how Cdc42 acts at the Golgi also suggests key issues for further clarification in the future (see Outstanding Questions).

First, whether

Acknowledgments

Work in the Farhan laboratory is funded by the Swiss National Science Foundation, the German Science Foundation, the Young Scholar Fund of the University of Konstanz, and the Biotechnology Institute Thurgau. Work in the Hsu laboratory is funded by the National Institutes of Health (GM058615).

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