High impact information on RAPGEF2

• Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation [1].
• The beta1 adrenergic receptor (beta1-AR) binds to the PDZ domain of the cyclic AMP (cAMP)-dependent Ras exchange factor, CNrasGEF, via its C-terminal SkV motif [1].
• Cyclic nucleotide ras GEF (CNrasGEF) is a guanine-nucleotide exchange factor previously isolated in a screen for Nedd4-WW domain interacting proteins (Pham, N., Cheglakov, I., Koch, C. A., de Hoog, C. L., Moran, M. F., and Rotin, D. (2000) Curr. Biol. 10, 555-558) [2].
• Deletion/mutation of the CDC25 domain to abrogate Ras (or Rap-1) binding leads to impaired ubiquitination of CNrasGEF, suggesting that such binding is critical for ubiquitination [2].
• CNrasGEF is also stabilized in cells co-expressing Nedd4(CS) or following treatment with lactacystin, indicating proteasomal degradation of this protein [2].

Biological context of RAPGEF2

• MR-GEF and PDZ-GEF both contain a region immediately N-terminal to their catalytic domains that share sequence homology with Ras-associating or RalGDS/AF6 homology (RA) domains [3].

Anatomical context of RAPGEF2

• CNrasGEF is expressed mainly in the brain and is localized at the plasma membrane, a localization dependent on the presence of intact PDZ domain but not the SxV sequence [4].
• In this study, we have examined whether MAGI-1/BAP1 also interacts with and serves as a scaffolding molecule for Rap GEP at tight junctions in epithelial cells [5].

Associations of RAPGEF2 with chemical compounds

• RA-GEF, a novel Rap1A guanine nucleotide exchange factor containing a Ras/Rap1A-associating domain, is conserved between nematode and humans [6].
• We named it nRap GEP (neural Rap GEP). nRap GEP moreover has an incomplete cyclic AMP (cAMP)-binding (CAB) domain [7].

Physical interactions of RAPGEF2

• RESULTS: MAGI-1/BAP1 similarly interacted with Rap GEP in cell-free and intact cell systems [5].

Regulatory relationships of RAPGEF2

• Interestingly, PDZ-GEF1 also activates Rap2, a close relative of Rap1 [8].

Other interactions of RAPGEF2

• By searching for in vitro interaction with Ras-GTP proteins, PDZ-GEF specifically bound to Rap1A- and Rap2B-GTP, whereas MR-GEF bound to M-Ras-GTP [3].
• We conclude that PDZ-GEF1 is a guanine nucleotide exchange factor, specific for Rap1 and Rap2, that is controlled by a negative regulatory domain [8].
• This activation is prevented in CNrasGEF lacking its CDC25 domain or cNMP-BD [4].

Analytical, diagnostic and therapeutic context of RAPGEF2

• Moreover, Nedd4 and CNrasGEF co-immunoprecipitate from 293T cells expressing ectopic CNrasGEF and endogenous Nedd4, and this co-immunoprecipitation is abrogated in PY motif-mutated CNrasGEF (CNrasGEFDelta2PY) [2].
• A Northern blot analysis revealed that Rap GEP was expressed in most tissues examined [5].

References