Abstract

The G12/13 class of heterotrimeric guanine-nucleotide binding proteins (G proteins) convert extracellular signals to intracellular responses including cell growth, oncogenic transformation, migration, and cytoskeletal rearrangement. Mammals possess two distinct alpha subunits within this G protein class, Gα12 and Gα13. Sequence divergence after duplication of the ancestral G12/13 gene has led Gα12 and Gα13 to evolve unique binding interactions with various target proteins in the cell such as Hsp90, ARAF, and Axin. These distinct effector interactions have allowed Gα12 and Gα13 to develop unique mechanisms for cell growth signaling through the serum response element pathway. Previous experiments revealed that a variable 42-residue region at the C terminus was necessary for growth signaling in Gα12 but not Gα13. In order to further investigate the functional role of this region in Gα12, several chimeric Gα13 proteins were constructed to contain G⍺12 sequence at regions of interest. Protein co-precipitation assays revealed that introducing the variable 42-residue region of Ga12 bestowed G⍺13 with the ability to bind to G⍺12-specific effector proteins. This finding suggests that sequence divergence in the variable region has allowed Gα12 to evolve distinct functional differences in effector binding that may contribute to its unique mechanism of growth signaling. Because certain cancers selectively overexpress Gα12 or Gα13, our further characterization of this region of Gα12 can be used to guide the development of Gα12-specific growth signaling inhibitors.

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