The G12 subfamily of heterotrimeric G proteins, comprising of Gα12 and Gα13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal change to cell growth and oncogenesis. They stimulate mitogenic signaling pathways leading to the oncogenic transformation of fibroblast cell lines. Gα12 and Gα13 regulate cytoplasmic as well as nuclear signaling events through downstream targets such as Ras, Rac, Rho, and CDC42 leading to cytoskeletal reorganization and activation of MAPK, JNK, the Na+-H+ exchanger, c-Fos, SRE and transcriptional activation of specific primary response genes.Gα12 and Gα13 induce Rho activation and Rho-dependent biological responses including stress fiber formation and focal adhesion assembly. Two novel RhoGEFs, PDZ-RhoGEF and LARG, interact with the activated α-subunits of G12/G13 and thus mediate GPCR-induced Rho activation. Gα12/13 stimulate small GTPases by stimulating specific GEFs, competing with GDIs, or inhibiting specific GAPs. Both Gα12 and Gα13 can physically interact with the RGS motif containing RhoGEF. Signal coupling between Gα13 and Rho involve RTKs such as EGFR and other non-receptor kinases. In contrast, the coupling between Gα12 and Rho is independent of any tyrosine kinases. Similarly, a role for BTK family of kinases in Gα12/13 coupling to Rho has been observed. Activated Rho induces the formation of actin stress fibers and promotes the assembly of focal adhesions.
GPCRs that activate Rho and use Gα12 or Gα13 for signal transduction include receptors for lysophosphatidic acid, sphingosine 1-phosphate, thrombin, thromboxane A2 and the orphan receptor G2A. PYK2 is itself activated by Gα13, and to a lesser extent by Gα12. The RGS domain of Lsc blocks activation of PYK2 by Gα12 and Gα13. Gα12 also physically interacts with a novel RasGAP as well as BTK and stimulates their activity. Gα12/13 coordinates several critical signaling events through its interaction with the Ras and Rho family of GTPases. These include the regulation of different kinase modules as well as the activation of several transcription factors such as SRFs, TCFs, Jun and ATF2. In many cases it appears that different members of the MAPK family such as ERK5 or JNK are activated. This activation leads to regulation of gene expression. Gα13, besides directly interacting with and activating Rho, also engages the PI3K pathway to activate the protein kinase AKT and regulates NF-κB, through the activation of PYK2.
Gα12 and Gα13 also interact with the cytoplasmic domains of several members of the cadherin family of cell surface adhesion proteins, causing dissociation of the transcriptional activator from cadherins. Among proteins previously found to associate with the cadherin cytoplasmic region, β-Ctnn is a multi-functional protein that not only serves to link cadherin to the actin cytoskeleton, but also serves as a transcriptional activator. These findings provide a potential molecular mechanism for the cellular transforming ability of Gα12/13 subfamily, and reveal a link between heterotrimeric G-proteins and cellular processes controlling growth and differentiation.