Determining Cellular Role of Gα12

Dermott, Jonathan M.; Dhanasekaran, N.

doi:10.1016/s0076-6879(02)44722-2

Cited by 8 publications

(18 citation statements)

References 15 publications

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“…The ability of LPA to substitute serum in stimulating Ga 12 -mediated JNK-response and DNA synthesis further supports the view that LPA is the primary factor underlying the previously identified serum-dependent neoplastic transformation by Ga 12 (Chan et al, 1993;Dermott and Dhanasekaran, 2002). Previous studies from different laboratories including ours have shown that the stimulation of the wild-type Ga 12 or overexpression of constitutively activated Ga 12 results in the robust activation of JNK in different cell types (Prasad et al, 1995;Collins et al, 1996;Voyno-Yasenetskaya et al, 1996).…”

supporting

confidence: 83%

“…While previous studies have demonstrated that LPA can stimulate Ga 12 (Gohla et al, 1998) NIH3T3 cells stably expressing Ga 12 WT show increased cell proliferation when grown in medium containing 5% calf serum (Figure 1a,b). Previous studies have shown that the proliferation and subsequent transformation of Ga 12 WT-NIH3T3 cells are fully contingent upon the presence of serum, whereas the mutational activation of Ga 12 abrogates such serumrequirement (Chan et al, 1993;Dermott and Dhanasekaran, 2002). This has been attributed to a growth factor that stimulates the expressed Ga 12 WT in these cells (Dermott and Dhanasekaran, 2002;Dermott et al, 2004).…”

mentioning

confidence: 98%

“…Previous studies have shown that the proliferation and subsequent transformation of Ga 12 WT-NIH3T3 cells are fully contingent upon the presence of serum, whereas the mutational activation of Ga 12 abrogates such serumrequirement (Chan et al, 1993;Dermott and Dhanasekaran, 2002). This has been attributed to a growth factor that stimulates the expressed Ga 12 WT in these cells (Dermott and Dhanasekaran, 2002;Dermott et al, 2004). Since LPA is a major GPCR-activating growth factor present in the serum (Moolenaar et al, 2004), we investigated whether LPA, through its respective GPCRs, stimulates Ga 12 in mediating the proliferation of these cells.…”

mentioning

confidence: 99%

“…Even Ga 13 , which shares 67% amino-acid identity with Ga 12 , is relatively weak in eliciting mitogenic response (Vara Prasad et al, 1994). In contrast, the ability to stimulate mitogenic response by serum-stimulated Ga 12 -WT as well as the activated mutant of Ga 12 (Ga 12 QL) is quite potent (Vara Prasad et al, 1994;Dermott and Dhanasekaran, 2002). It is significant to note that the transforming activity of Ga 12 is comparable only to that of the activated mutants of H-ras (Vara Prasad et al, 1994).…”

mentioning

confidence: 99%

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Mitogenic signaling by lysophosphatidic acid (LPA) involves Gα12

Radhika

Jayaraman

et al. 2005

Oncogene

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Lysophosphatidic acid (LPA), a major G protein coupled receptor (GPCR)-activating ligand present in serum, elicits growth factor like responses by stimulating specific GPCRs coupled to heterotrimeric G proteins such as G i , G q , and G 12/13 . Previous studies have shown that the overexpression of wild-type Ga 12 (Ga 12 WT) results in the oncogenic transformation of NIH3T3 cells (Ga 12 WT-NIH3T3) in a serum-dependent manner. Based on the potent growth-stimulating activity of LPA and the presence of LPA and LPA-like molecules in the serum, we hypothesized that the serum-dependent neoplastic transformation of Ga 12 WT-NIH3T3 cells was mediated by the stimulation of LPA-receptors (LPARs) by LPA in the serum. In the present study, using guanine nucleotide exchange assay and GST-TPR binding assay, we show that the treatment of Ga 12 WT-NIH3T3 with 2 lM LPA leads to the activation of Ga 12 . Stimulation of these cells with LPA promotes JNK-activation, a critical component of Ga 12 -response and cell proliferation. We also show that LPA can substitute for serum in stimulating JNK-activity, DNA synthesis, and proliferation of Ga 12 WT-NIH3T3 cells. LPA-mediated proliferative response in NIH3T3 cells involves Ga 12 , but not the closely related Ga 13 . Pretreatment of Ga 12 WT-NIH3T3 cells with suramin (100 lM), a receptor-uncoupling agent, inhibited LPAstimulated proliferation of these cells by 55% demonstrating the signal coupling between cell surface LPAR and Ga 12 in the neoplastic proliferation of NIH3T3 cells. 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, Ga 12 , and the downstream effectors is likely to unravel additional targets for novel cancer chemotherapies.

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supporting

confidence: 83%

mentioning

confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mitogenic signaling by lysophosphatidic acid (LPA) involves Gα12

Radhika

Jayaraman

et al. 2005

Oncogene

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“…Our previous studies have shown that the stimulation of the wild-type Ga 12 (Ga 12 -WT) or the expression of Ga 12 QL results in the robust activation of JNK (Dermott and Dhanasekaran, 2002). In the present study, we describe for the first time that the stimulation of Ga 12 WT or the expression of Ga 12 QL leads to the inhibition of p38MAPK.…”

Section: Introductionmentioning

confidence: 49%

Differential regulation of Jun N-terminal kinase and p38MAP kinase by Gα12

Dermott

Lee

et al. 2004

Oncogene

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Based on the findings that the overexpression of the wildtype Ga 12 (Ga 12 WT) result in the oncogenic transformation of NIH3T3 cells in a serum-dependent manner, a model system has been established in which the mitogenic and subsequent cell transformation pathways activated by Ga 12 can be turned on or off by the addition or removal of serum. Using this model system, our previous studies have shown that the stimulation of Ga 12 WT or the expression of an activated mutant of Ga 12 (Ga 12 QL) leads to increased cell proliferation and subsequent oncogenic transformation of NIH3T3 cells, as well as persistent activation of Jun N-terminal kinases (JNKs). In the present studies, we show that the stimulation of Ga 12 WT or the expression of Ga 12 QL results in a potent inhibition of p38MAPK, and that the mechanism by which Ga 12 inhibits p38MAPK activity involves the dual specificity kinases upstream of p38MAPK. The results indicate that Ga 12 attenuates the activation of MKK3 and MKK4, which are known to stimulate only p38MAPK or p38MAPK and JNK, respectively. The results also suggest that Ga 12 activates JNKs specifically through the stimulation of the JNK-specific upstream kinase MKK7. These findings demonstrate for the first time that Ga 12 differentially regulates JNK and p38MAPK by specifically activating MKK7, while inhibiting MKK3 and MKK4 in NIH3T3 cells. Since the stimulation of p38MAPK is often associated with apoptotic responses, our findings suggest that Ga 12 stimulates cell proliferation and neoplastic transformation of NIH3T3 cells by attenuating p38MAPK-associated apoptotic responses, while activating the mitogenic responses through the stimulation of ERK-and JNK-mediated signaling pathways.

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