rap1 p21 regulates the interaction of ras p21 with RGL, a new effector protein of ras p21

Abstract

We have recently found that ralGDS family members (RGL and ralGDS) are putative effector proteins of ras p21. rapl p21 is a small GTP-binding protein which has the same amino acid sequence as the effector loop of ras p21. We examined the effect of rapl p21 on the interaction of ras p21 with RGL. The GTP-bound form of rapl p21 interacted with RGL as well as did ras p21. rapl p21 inhibited the interaction of ras p21 with RGL. RGL was phosphorylated by cyclic AMP-dependent protein kinase (protein kinase A). Phosphorylation of RGL did not affect its binding to ras p21 and rapl p21 under the conditions that phosphorylation of Raf-1 reduced its affinity for ras p21. These results demonstrate that rapl p21 but not protein kinase A regulates the interaction of ras p21 with RGL and suggest that rapl p21 and protein kinase A may cooperate to distinguish the signal of ras p21 to RGL from that to Raf-1.

Manumycin inhibits ras signal transduction pathway and induces apoptosis in COLO320-DM human colon tumourcells

“…These proteins undergo geranylgeranylation by the geranylgeranyl: protein transferase I; as a matter of fact, the results demonstrated that their post-translational modification was not affected by manumycin. The p21rhoA protein has a role in the regulation of focal adhesion processes, differentiation and signal transduction via integrins (Giancotti and Mainiero, 1994), while p21rap1 protein is physiological inhibitor of p21ras function (Ikeda et al, 1995;Nassar et al, 1995;Wittinghofer and Herrman, 1995). Therefore, the prevalence of p21rap1 function over the inhibited p21ras may be an additional factor contributing to the overall activity of manumycin.…”

Crk family adaptors–signalling complex formation and biological roles

“…However, many of these studies report Crk/CRKL-independent activation of Rap1 and the B-Raf protein is not expressed in many cell types where Crk ± C3G ± Rap1 signal signalling activity has been detected. Other possible candidates need to be analysed in much more detail, for example the Ral ± GDS-like proteins RGL and RGL-2 (Ikeda et al, 1995;Peterson et al, 1996) and the Ral ± GDS-like factor (Rlf) (Wolthuis et al, 1996), but also more recently found candidates like the cell junctional multidomain protein AF-6 (Boettner et al, 2000) and RGS14, a member of the`regulator of Gprotein signalling' family (Traver et al, 2000). Activation of the`stress kinase' JNK by Crk and C3G (Tanaka et al, 1997;Dol® et al, 1998;Tanaka and Hanafusa, 1998;Zhu et al, 1998) has also been reported, but how this exactly occurs remains to be de®ned although a recent report suggests that R-Ras rather than Rap1 may be responsible for this.…”

Activation of the Rap1 Guanine Nucleotide Exchange Gene,CalDAG-GEF I, in BXH-2 Murine Myeloid Leukemia

“…This would suggest that Rap1 signals suppress rather than promote oncogenesis. Later publications (35)(36)(37) showed that the Rap1 effector domain, being virtually identical to that of Ras, can bind to many Ras effectors without activating them. These data have led to the hypothesis that Rap1 serves as a Ras antagonist by sequestering Ras effectors.…”

“…Rap1 signaling has been shown to activate the mitogen-activated protein kinase pathway independently of Ras signaling via B-Raf (52,53). In addition, Rap1-GTP, like Ras can bind to the Ral guanine exchange factors RalGDS and Rgl1 (35,36). The function of Ral-GTP is not known, but Ral dominant-negative mutants block R-Ras-induced adhesion to fibronectin in 32D cells (51).…”