Characterisation of PDZ-GEFs, a family of guanine nucleotide exchange factors specific for Rap1 and Rap2

Biochim Biophys Acta. 2003 Feb 17;1593(2-3):141-9. doi: 10.1016/s0167-4889(02)00365-8.


PDZ-GEF1 (RA-GEF/nRapGEP/CNrasGEF) is a guanine nucleotide exchange factor (GEF) characterised by the presence of a PSD-95/DlgA/ZO-1 (PDZ) domain, a Ras-association (RA) domain and a region related to a cyclic nucleotide binding domain (RCBD). These domains are in addition to a Ras exchange motif (REM) and GEF domain characteristic for GEFs for Ras-like small GTPases. PDZ-GEF1 efficiently exchanges nucleotides of both Rap1 and Rap2, but has also been implicated in mediating cAMP-induced Ras activation through binding of cAMP to the RCBD. Here we describe a new family member, PDZ-GEF2, of which we isolated two splice variants (PDZ-GEF2A and 2B). PDZ-GEF2 contains, in addition to the domains characteristic for PDZ-GEF1, a second, less conserved RCBD at the N-terminus. PDZ-GEF2 is also specific for both Rap1 and Rap2. We further investigated the possibility that PDZ-GEF2, like PDZ-GEF1, is a cAMP-responsive GEF for Ras. However, in contrast to previous results, we did not find any effect of either PDZ-GEF1 or PDZ-GEF2 on Ras in the absence or presence of cAMP. Moreover, affinity measurements by isothermic calorimetry showed that the RCBD of PDZ-GEF1 does not bind cAMP with a physiologically relevant affinity. We conclude that both PDZ-GEF1 and 2 are specific for Rap1 and Rap2 and unresponsive to cAMP and various other nucleotides.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Cloning, Molecular
  • Cyclic AMP / pharmacology
  • Guanine Nucleotide Exchange Factors / biosynthesis
  • Guanine Nucleotide Exchange Factors / chemistry
  • Guanine Nucleotide Exchange Factors / genetics*
  • Mice
  • Molecular Sequence Data
  • Nerve Tissue Proteins*
  • rap GTP-Binding Proteins / metabolism
  • rap1 GTP-Binding Proteins / metabolism*


  • Guanine Nucleotide Exchange Factors
  • Nerve Tissue Proteins
  • RAPGEF2 protein, human
  • Cyclic AMP
  • Rap2a protein, mouse
  • rap GTP-Binding Proteins
  • rap1 GTP-Binding Proteins

Associated data

  • GENBANK/AF478468
  • GENBANK/AF478469