Comparative Interaction of Cadherin Cell Adhesion Proteins with Guanine Nucleotide-Binding Proteins Ga12 and Ga13

Jonathan Sims


Cell migration, proliferation, and attachment are critical processes for both normal tissue growth, and the development of malignant disease.  The G12/13 class of heterotrimeric guanine nucleotide-binding (G) proteins and their interaction with cadherin cell adhesion proteins has been implicated in the regulation of these processes.  The two members of the G12/13 class, Ga12 and Ga13 are structurally similar, sharing 67% amino acid homology, but show only partial overlap in effector signaling.1 Previous work demonstrated that Ga12 binds an acidic 11 amino acid region of the cytoplasmic C-terminal domain of epithelial (E)-cadherin, a membrane spanning cell adhesion protein responsible for adherens junction formation. This interaction was shown to cause cell disassociation and cell migration,2 a hallmark of metastasis. While this region of E-cadherin was implicated in this binding event, the interacting residues and affinities of Ga12 and Ga13 with E-cadherin and other cadherin family members have yet to be elucidated.  Here, epitope tagged mutants of Ga12 and chimeric constructs of Ga12 and Ga13 were used to examine binding affinities of these proteins with several members of the cadherin family.  Interestingly, the activated form of Ga12 had a higher affinity for all cadherins tested when compared to Ga13, suggesting Ga12 may play a larger role in the regulation of these cell adhesion proteins.  Pursuant to previous investigations, six sextet cassette mutants of eGFP tagged activated Ga12QL spanning the switch region I were utilized to examine binding to E-cadherin and VE-cadherin, which surprisingly failed to uncouple interaction.  The E-cadherin deletion mutant that lacks the 11 amino acid region and had been demonstrated to disrupt binding of Ga122 was tested alongside Ga13 and strikingly showed strong binding to Ga12QL but abrogated binding to Ga13QL.  These data show that a potentially different activational conformation exists between Ga12QL and Ga13QL, but that both G proteins bind a common region of the cytoplasmic domain of E-cadherin.


Ga12/13, Cadherins, cancer

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