Biology of the Rap proteins, members of the ras superfamily of GTP-binding proteins.

A large superfamily (> 50 members) of monomeric GTPbinding proteins structurally related to the ras oncogene proteins has been described in the past few years (Bourne et al., 1991; Grand and Owen, 1991; Hall, 1990; Valencia et al., 1991). These proteins have been implicated in the regulation of a diverse array of cellular processes, utilizing their ability to bind and hydrolyse GTP as a means to regulate the reversible interactions and/or activities of macromolecules involved in these processes. Based upon sequence homology, the ras superfamily can be divided into four subfamilies, ras, rho, rab and arf(Valencia et al., 1991; Kahn et al., 1992). The ras proteins are essential components of receptor-mediated signaling pathways controling cell proliferation and differentiation; the rho proteins are involved in cytoskeletal assembly and NADPH oxidase regulation in phagocytes; and the rab and arf proteins regulate the transport of vesicles between intracellular compartments and/or the plasma membrane (see Hall, 1990). The mammalian rap proteins, which are the focus of this Review, are members of the ras family of GTP-binding proteins,and share highly conserved structural motifs with the ras transforming proteins. Overall, the rap proteins share -50% sequence similarity with ras and, like ras, are found in nearly all tissues. Two rap families, designated rapl and rap2, have been identified to date. Within each family are two members denoted as A and B, i.e. raplA and raplB (see Figure 1). As is the case with the majority of the low-molecular-mass GTP-binding proteins, the actual role(s) of the Rap proteins in cellular function have not yet been elucidated in detail. There is evidence however that Rap proteins exert biological activities in at least two cellular arenas: first in that of cellular growth and differentiation control, and secondly in a phagocyte-specific enzyme system responsible for the generation of microbicidal oxygen radicals. The latter suggests either that Rap can play very specific biological roles in certain cells or, alternatively, that Rap serves a very general function which can involve different proteins and different effector systems depending on the cell involved. In this Review, I examine current knowledge of the biology of the Rap proteins.