2768

GNA12

guanine nucleotide binding protein (G protein) alpha 12;GNA12;guanine nucleotide binding protein (G protein) alpha 12

G-protein subunit alpha-12|WUGSC:H_GS165O14.2|g alpha-12|guanine nucleotide-binding protein subunit alpha-12

7p22.2

protein-coding

The G12 subfamily of heterotrimeric guanine nucleotide-binding proteins consists of two alpha subunits, G alpha12 and G alpha13. These proteins mediate signalling via G protein-coupled receptors and have been implicated in various physiological and pathophysiological processes. A number of direct and indirect effectors of G alpha12 and G alpha13 have been identified that mediate, or have been proposed to mediate, the diverse cellular responses accompanying activation of G12 proteins. This review describes the signalling pathways and cellular events stimulated by G12 proteins, with a particular emphasis on processes that are important in regulating cell migration and invasion, and could potentially be involved in the pathophysiology of cancer metastasis. Experimental findings directly implicating G12 proteins in the spread of metastatic disease are also summarized, indicating the importance of targeted inhibition of G12 signalling as a potential therapeutic option for locally advanced and metastatic disease.

Many studies have suggested a role for the members of the G12 family of heterotrimeric G proteins (Galpha12 and Galpha13) in oncogenesis and tumor cell growth. However, few studies have examined G12 signaling in actual human cancers. In this study, we examined the role of G12 signaling in prostate cancer. We found that expression of the G12 proteins is significantly elevated in prostate cancer. Interestingly, expression of the activated forms of Galpha12 or Galpha13 in the PC3 and DU145 prostate cancer cell lines did not promote cancer cell growth. Instead, expression of the activated forms of Galpha12 or Galpha13 in these cell lines induced cell invasion through the activation of the RhoA family of G proteins. Furthermore, inhibition of G12 signaling by expression of the RGS domain of the p115-Rho-specific guanine nucleotide exchange factor (p115-RGS) in the PC3 and DU145 cell lines did not reduce cancer cell growth. However, inhibition of G12 signaling with p115-RGS in these cell lines blocked thrombin- and thromboxane A2-stimulated cell invasion. These observations identify the G12 family proteins as important regulators of prostate cancer invasion and suggest that these proteins may be targeted to limit invasion- and metastasis-induced prostate cancer patient mortality.