Disease relevance of Gna13

• Galpha12 and Galpha13 mediate differentiation of P19 mouse embryonal carcinoma cells in response to retinoic acid [1].
• These findings, along with the observation that Hax-1 is overexpressed in metastatic tumors and tumor cell lines, suggest a novel role for the association of oncogenic Galpha13 and Hax-1 in tumor metastasis [2].
• In this study, we report that signaling through the G12 family of heterotrimeric G proteins (Galpha12 and Galpha13) promotes breast cancer cell invasion [3].
• Galpha13 activation rescues moesin-depletion induced apoptosis in F9 teratocarcinoma cells [4].
• Phospholipase D activation by endogenous 5-hydroxytryptamine 2C receptors is mediated by Galpha13 and pertussis toxin-insensitive Gbetagamma subunits [5].

High impact information on Gna13

• Disruption of the gene encoding the G protein subunit alpha13 (Galpha13) in mice impaired the ability of endothelial cells to develop into an organized vascular system, resulting in intrauterine death [6].
• In addition, Galpha13 (-/-) embryonic fibroblasts showed greatly impaired migratory responses to thrombin [6].
• These results demonstrate that Galpha13 participates in the regulation of cell movement in response to specific ligands, as well as in developmental angiogenesis [6].
• Moreover, expression of Galpha12 and Galpha13 stimulates autophosphorylation and transphosphorylation activities of Tec [7].
• 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 [8].

Biological context of Gna13

• We have shown that a constitutively active Galpha13 (Galpha13Q226L) induces differentiation in P19 embryonic carcinoma cells to an endodermal phenotype [9].
• Essential role for Galpha13 in endothelial cells during embryonic development [10].
• Deficiency of either Galpha12 or Galpha13 increases programmed cell death [1].
• Thus, both Galpha12 and Galpha13 are essential to stimulation of cell differentiation by retinoic acid [1].
• We determined that Galpha13-dependent VASP phosphorylation was also inhibited by specific PKA inhibitors, PKI and H-89 [11].

Anatomical context of Gna13

• G alpha 13 signals via p115RhoGEF cascades regulating JNK1 and primitive endoderm formation [12].
• Differential involvement of Galpha12 and Galpha13 in receptor-mediated stress fiber formation [13].
• Whereas these observations point to the vital role of G13-orthologs in regulating cell migration, widely across the species barrier, the mechanism by which Galpha13 couples to cytoskeleton and cell migration is largely unknown [2].
• G alpha 12 and G alpha 13 stimulate Rho-dependent stress fiber formation and focal adhesion assembly [14].
• Galpha13 mediates the ability of the morphogen retinoic acid to promote primitive endoderm formation from mouse P19 embryonal carcinoma stem cells, a process that includes the obligate activation of Jun N-terminal kinase [15].

Associations of Gna13 with chemical compounds

• Guanine nucleotide exchange factor GEF115 specifically mediates activation of Rho and serum response factor by the G protein alpha subunit Galpha13 [16].
• Expression of the constitutively active form of Galpha13 (Q226L) stimulates differentiation of the cells from embryonal to endodermal, in the absence of retinoic acid [1].
• The tyrosine kinase inhibitor tyrphostin A25 blocked the neurite retraction and cell rounding induced by Galpha13 and Galphaq [17].
• G alpha 13 increased bradykinin-stimulated Ca influx by a mechanism that depends on NO and cGMP [18].
• To determine which G-proteins are implicated in the U46619-induced IL-6 synthesis, the interfering mutants of Galpha(q), Galpha12, or Galpha13 by were overexpressed in 1321N1 cells adenoviral approach [19].

Physical interactions of Gna13

• Expression of Hax-1 reduces the formation of actin stress fibers and focal adhesion complexes in Galpha13-expressing NIH3T3 cells [2].
• Structure of the p115RhoGEF rgRGS domain-Galpha13/i1 chimera complex suggests convergent evolution of a GTPase activator [20].

Regulatory relationships of Gna13

• These results demonstrate that Galpha13 can induce cellular transformation through pathways apparently independent of the IGF-I receptor and that activation of the IGF-I receptor signaling pathways, although not essential for the transforming phenotype, enhances the effect of other pathways [21].
• Dominant negative forms of MEKK1 and MEKK4 were expressed stably in the clones harboring Q226L Galpha13 [15].
• Activated mutant of G alpha 13 induces Egr-1, c-fos, and transformation in NIH 3T3 cells [22].
• 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].
• G alpha q and G alpha 13 regulate NHE-1 and intracellular calcium in epithelial cells [24].

Other interactions of Gna13

• The first inner loop of endothelin receptor type B is necessary for specific coupling to Galpha 13 [25].
• Radixin stimulates Rac1 and Ca2+/calmodulin-dependent kinase, CaMKII: cross-talk with Galpha13 signaling [26].
• These results suggest that Ku80 is required for Galpha13-mediated endodermal differentiation in P19 cells [9].
• Endothelial-specific Galpha13 knockout embryos died at embryonic days 9.5-11.5 and resembled the PAR1 knockout [10].
• The synergism between Galpha13 and GEF115 indicates that GEF115 mediates Galpha13-induced activation of Rho and SRF [16].

Analytical, diagnostic and therapeutic context of Gna13

• Northern blots of multiple clones revealed the expression of a 1.8-kilobase pair mutant Galpha13 transcript in transfected cells, in addition to the 6-kilobase pair endogenous mRNA [21].
• The transfection resulted in a doubling of the expression of Galpha13 protein in these cells as assessed by Western blot analysis [21].
• The interaction was demonstrated by (i) the binding of G alpha 13 to immobilized beta gamma-complexes and (ii) the formation of stable heterotrimers during sucrose-density-gradient centrifugation [27].

References