Regulation of RhoGEF proteins by G12/13-coupled receptors

Br J Pharmacol. 2009 Sep;158(1):41-9. doi: 10.1111/j.1476-5381.2009.00121.x. Epub 2009 Feb 18.


G protein-coupled receptors (GPCRs) represent a large family of seven transmembrane receptors, which communicate extracellular signals into the cellular lumen. The human genome contains 720-800 GPCRs, and their diverse signal characteristics are determined by their specific tissue and subcellular expression profiles, as well as their coupling profile to the various G protein families (G(s), G(i), G(q), G(12)). The G protein coupling pattern links GPCR activation to the specific downstream effector pathways. G(12/13) signalling of GPCRs has been studied only recently in more detail, and involves activation of RhoGTPase nucleotide exchange factors (RhoGEFs). Four mammalian RhoGEFs regulated by G(12/13) proteins are known: p115-RhoGEF, PSD-95/Disc-large/ZO-1 homology-RhoGEF, leukemia-associated RhoGEF and lymphoid blast crisis-RhoGEF. These link GPCRs to activation of the small monomeric GTPase RhoA, and other downstream effectors. Misregulated G(12/13) signalling is involved in multiple pathophysiological conditions such as cancer, cardiovascular diseases, arterial and pulmonary hypertension, and bronchial asthma. Specific targeting of G(12/13) signalling-related diseases of GPCRs hence provides novel therapeutic approaches. Assays to quantitatively measure GPCR-mediated activation of G(12/13) are only emerging, and are required to understand the G(12/13)-linked pharmacology. The review gives an overview of G(12/13) signalling of GPCRs with a focus on RhoGEF proteins as the immediate mediators of G(12/13) activation.

Publication types

  • Review

MeSH terms

  • Animals
  • GTP-Binding Protein alpha Subunits, G12-G13 / chemistry
  • GTP-Binding Protein alpha Subunits, G12-G13 / physiology*
  • Guanine Nucleotide Exchange Factors / chemistry
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / physiology
  • Rho Guanine Nucleotide Exchange Factors
  • Signal Transduction / physiology


  • ARHGEF1 protein, human
  • Guanine Nucleotide Exchange Factors
  • Receptors, G-Protein-Coupled
  • Rho Guanine Nucleotide Exchange Factors
  • GTP-Binding Protein alpha Subunits, G12-G13