Rab GTPases: master regulators that establish the secretory and endocytic pathways

Abstract

Several of the most important discoveries in the field of membrane traffic have come from studies of Rab GTPases by Marino Zerial and Peter Novick and their colleagues. Zerial was the first to discover that Rab GTPases represent identity markers for different membrane-bound compartments, and each Rab organizes a collection of specific effectors into function-specifying membrane microdomains to carry out receptor trafficking. Novick discovered that the order (and thus polarity) of Rab GTPases along the secretory and endocytic pathways are established by their specific, cognate guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), which partner with one Rab to regulate the subsequent- and prior-acting Rabs. Such so-called Rab cascades have evolved to establish domains that contain unique Rab proteins and their cognate effectors, which drive all steps of membrane trafficking. These findings deserve much broader recognition by the biomedical research community and are highlighted here, along with open questions that require serious attention for full understanding of the molecular basis of Rab GTPase-regulated membrane trafficking in eukaryotic cells.

FIGURE 1:

Rab cascade model for the establishment and maintenance of the polarity of the secretory and endocytic pathways. (A) In the first scenario, a Rab GEF specific for Rab A generates active Rab A. That Rab recruits a second GEF, which activates Rab B. Similarly, Rab B recruits a GEF to activate Rab C. In this model, a membrane could have Rabs A–C intermingled or at least on a single compartment. (B) Here GAP proteins are included to remove a previous-acting Rab from a specific membrane domain. The presence of the GAP will sharpen the boundaries between individual Rab domains. Data of Rivera-Molina and Novick (2009) support the model in B. Reprinted from Nottingham and Pfeffer (2009).