Specificity in Ras and Rap signaling

Abstract

Ras and Rap proteins are closely related small GTPases. Whereas Ras is known for its role in cell proliferation and survival, Rap1 is predominantly involved in cell adhesion and cell junction formation. Ras and Rap are regulated by different sets of guanine nucleotide exchange factors and GTPase-activating proteins, determining one level of specificity. In addition, although the effector domains are highly similar, Rap and Ras interact with largely different sets of effectors, providing a second level of specificity. In this review, we discuss the regulatory proteins and effectors of Ras and Rap, with a focus on those of Rap.

FIGURE 1.

Ras and Rap effector proteins and GEFs. A schematic representation is shown of the domain structures of Ras and Rap GEFs and effector proteins discussed here. RA domains/RBDs are depicted in pink, catalytic domains in blue, lipid-binding domains in green, and other domains in yellow. Asterisks indicate domains required for Ras/Rap binding. C1, protein kinase C conserved region 1; C2, Ca²⁺-binding motif; PIK, PI3K accessory domain; PI3Kc, PI3K catalytic domain; CDC25, CDC25 homology; FHA, Forkhead-associated domain; DIL, dilute; Ank, ankyrin repeat; CH, calponin homology; SAM, sterile α-motif; cNBD, cyclic nucleotide-binding domain; PLCXY, phospholipase C catalytic regions X and Y; DEP, Dishevelled/Egl-10/pleckstrin; EF, EF-hand; histone, histone domain. 1) The interaction of Tiam1 with Ras has been described for the RBD; for Rap, it was shown to bind to the DH-PH domain. 2) The N-terminal cyclic nucleotide-binding domain is conserved in Epac2 alone, and the RA domain-like sequence in Epac1 is not recognized as such by the SMART Database (smart.embl-heidelberg.de). 3) Although described to be present in PLCε (18, 45), a second RA domain in PLCε is not indicated in the SMART Database.