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Wednesday, April 22 • 9:00am - 9:20am
β3 Integrin Interaction with Guanine Nucleotide-Binding Proteins Gα12 and Gα13

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Cell attachment, migration, and proliferation are essential processes for both normal tissue growth and malignant development. Guanine nucleotide-binding (G) proteins and integrins play key roles in the regulation of these processes. The G proteins Gα12 and Gα13 have 66% amino acid homology, yet differ in their downstream signaling function. While these proteins have been extensively studied in their own roles, the mechanisms by which they interact have only been partially examined.  Other investigators have shown C-terminal binding of β3 integrin to Gα13, but not Gα12. Utilizing epitope-tagged forms of Gα12 and Gα13, we examined their affinity for β3 integrin. We found that Gα12 showed greater binding affinity for β3 integrin than did Gα13, in both myc- and GFP-tagged forms. Furthermore, we utilized constitutively active and inactive forms of Ga12 and Gα13, as well as wild-type Gα12/13, to determine if this differential was due to the activation state. For Gα13, β3 integrin did not differ in affinity for the QL or wild type, and still showed no binding overall. Yet for Gα12, β3 integrin exhibited stronger binding for the GTP-bound form than the wild-type or GDP-bound forms. These findings suggest that Gα12 must be in the GTP-bound form to adequately bind β3 integrin in cells. Lastly, we tested NAAIRS sextet mutations to attain greater knowledge of specific structural features of Gα12 required for interaction with β3 integrin (Richie et al. 2013). Surprisingly, we found that two amino acid substitution mutants of Gα12 exhibited impaired binding to β3 integrin. This provides new structural details and serves as a basis for further research in examining these regions to specifically identify the properties that disallow binding action. As both Gα12 and Gα13 have been implicated in cancer pathways, understanding these interactions is critical for complete appreciation of the metastatic potential of epithelial cancer cells.

Wednesday April 22, 2015 9:00am - 9:20am PDT
014 Zeis Hall