Disease relevance of Gna12

• Our results indicate that it is cell type independent as the transient expression of Galpha12QL or the activation of Galpha12-coupled receptors stimulates the expression of PDGFRalpha in NIH 3T3 as well as in human astrocytoma 1321N1 cells [1].
• Galpha12 and Galpha13 mediate differentiation of P19 mouse embryonal carcinoma cells in response to retinoic acid [2].
• Finally, we demonstrate that the expression of Galpha12 is significantly up-regulated in the earliest stages of breast cancer, implying that amplification of G12 signaling may be an early event in breast cancer progression [3].
• Initial experiments were designed to examine the role of pertussis toxin-sensitive G proteins, namely Galphai/o, as well as pertussis toxin-insensitive G proteins, namely Galpha12/13, in 5-HT-induced AA release [4].

High impact information on Gna12

• Here we demonstrate that Galphas and Galphai, but neither Galphaq, Galpha12 nor Gbetay, directly stimulate the kinase activity of downregulated c-Src [5].
• In mouse embryonic fibroblasts, the pSLIK platform was used to conditionally deplete the expression of the heterotrimeric G proteins Galpha12 and Galpha13 both singly and in combination, demonstrating the Galpha13 dependence of serum response element-mediated transcription [6].
• The DH-domain-deletion mutant also suppressed thrombin- and lysophosphatidic acid-induced SRF activation in NIH 3T3 cells, probably by inhibition of Galpha12/13 [7].
• Transactivation of platelet-derived growth factor receptor alpha by the GTPase-deficient activated mutant of Galpha12 [1].
• Using microarray analysis, we have previously identified a role for platelet-derived growth factor receptor alpha (PDGFRalpha) in Galpha12-mediated cell growth (R. N. Kumar et al., Cell Biochem. Biophys. 41:63-73, 2004) [1].

Biological context of Gna12

• Expression of the constitutively active, mutant form of Galpha12 (Q229L), in contrast, stimulates loss of the embryonal phenotype [2].
• Deficiency of either Galpha12 or Galpha13 increases programmed cell death [2].
• Thrombin induces nitric-oxide synthase via Galpha12/13-coupled protein kinase C-dependent I-kappaBalpha phosphorylation and JNK-mediated I-kappaBalpha degradation [8].
• Thus, both Galpha12 and Galpha13 are essential to stimulation of cell differentiation by retinoic acid [2].
• Stimulation of these cells with LPA promotes JNK-activation, a critical component of Galpha12-response and cell proliferation [9].

Anatomical context of Gna12

• Differential involvement of Galpha12 and Galpha13 in receptor-mediated stress fiber formation [10].
• The following heterotrimeric G protein mRNA transcripts were present in oocytes, eggs, or preimplantation embryos: G alpha q family (q, 11, and 14), G alpha 12 family (12 and 13), G alpha i family (i1, i2, i3, t2, z, and s), beta subunits 1, 2, 4, and 5, and gamma subunits 2, 3, 5, and 7 [11].
• Consistently, activating mutations for G proteins of the Galphas and Galphai2 families were found in human tumors; and members of the Galphaq and Galpha12 families are fully transforming when expressed in murine fibroblasts [12].
• Activation of RhoA by lysophosphatidic acid and Galpha12/13 subunits in neuronal cells: induction of neurite retraction [13].
• Galpha12/13-deficient cells lack Dia1 localization to the wound edge and are unable to form orientated, stable microtubules during wound healing [14].

Associations of Gna12 with chemical compounds

• Therefore, the thrombin, LPA, thromboxane A2, and endothelin receptors may be able to couple to Galpha12/13 [15].
• G alpha 12/13- and reactive oxygen species-dependent activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase by angiotensin receptor stimulation in rat neonatal cardiomyocytes [16].
• Pretreatment of Galpha12WT-NIH3T3 cells with suramin (100 microM), a receptor-uncoupling agent, inhibited LPA-stimulated proliferation of these cells by 55% demonstrating the signal coupling between cell surface LPAR and Galpha12 in the neoplastic proliferation of NIH3T3 cells [9].
• In the present study, using guanine nucleotide exchange assay and GST-TPR binding assay, we show that the treatment of Galpha12WT-NIH3T3 with 2 muM LPA leads to the activation of Galpha12 [9].
• However, tyrphostin A25 failed to inhibit the Galpha12-induced neuronal morphological changes [17].

Regulatory relationships of Gna12

• Thus, we demonstrate that GSK-3 is activated by both Galpha12 and Galpha13 in neuronal cells [18].

Other interactions of Gna12

• Differential regulation of Jun N-terminal kinase and p38MAP kinase by Galpha12 [19].
• CCK-A receptor activates RhoA through G alpha 12/13 in NIH3T3 cells [20].
• The GTPase-deficient, activated mutant of Galpha12 (Galpha12Q229L, or Galpha12QL) induces neoplastic growth and oncogenic transformation of NIH 3T3 cells [1].
• Wild type Galpha12 showed similar stimulatory effects on cyclin A promoter activity and E2F-mediated transactivation, although of lesser magnitude [21].
• In contrast, dominant negative Rac (N17Rac1) inhibited JNK activation by Galpha12 in HEK293 cells as well as three other cell lines [22].

Analytical, diagnostic and therapeutic context of Gna12

• As LPA and LPAR mediated mitogenic pathways have been shown to play a major role in tumor genesis and progression, a mechanistic understanding of the signal coupling between LPAR, Galpha12, and the downstream effectors is likely to unravel additional targets for novel cancer chemotherapies [9].
• In Swiss 3T3 cells, incubation with LPA or microinjection of constitutively active mutants of Galpha12 and Galpha13 induced formation of actin stress fibers and assembly of focal adhesions in a Rho-dependent manner [23].

References