P‐REX2, a novel PI‐3‐kinase sensitive Rac exchange factor

Rosenfeldt, Hans; Vázquez‐Prado, José; Gutkind, J. Silvio

doi:10.1016/j.febslet.2004.06.097

Cited by 90 publications

(90 citation statements)

References 16 publications

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“…PREX2 has been previously reported to act as an inhibitor of PTEN and an activator of the PI3K signaling pathway (15). However, the effect of PREX2 on PTEN and PI3K signaling has never been reported in pancreatic cancer.…”

Section: Promoting Role Of Prex2 In Pancreatic Cancer Cell Migrationmentioning

confidence: 85%

“…PREX2 is able to inhibit the activity of PTEN by directly binding to PTEN through its guanine nucleotide exchange factor domains. Through inhibition of PTEN activity, PREX2 is capable of activating the downstream PI3K signaling pathway (15,16). Indeed, it has been reported that knockdown of PREX2 inhibits the invasion and clonogenicity of gastric cancer cells via inhibition of PI3K signaling (17).…”

Section: Introductionmentioning

confidence: 99%

“…However, PTEN is frequently mutated or its activity is downregulated in human cancer (13,14). Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger factor 2 (PREX2) is a regulator of the small guanosine triphosphatase Rac, and has recently been reported to act as an inhibitor of PTEN (15,16). PREX2 is able to inhibit the activity of PTEN by directly binding to PTEN through its guanine nucleotide exchange factor domains.…”

Section: Introductionmentioning

confidence: 99%

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PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway

et al. 2016

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Abstract. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger factor 2 (PREX2) is a novel regulator of the small guanosine triphosphatase Rac, and has been observed to be implicated in human cancer by inhibiting the activity of phosphatase and tensin homolog (PTEN), thus upregulating the activity of the phosphoinositide 3-kinase (PI3K) signaling pathway. However, the exact role of PREX2 in pancreatic cancer has not been reported to date. In the present study, the expression levels of PREX2 were observed to be frequently increased in pancreatic cancer specimens compared with those in their matched adjacent normal tissues. In addition, PREX2 expression was also frequently upregulated in several pancreatic cancer cell lines, including AsPC-1, BxPC-3, PANC-1 and CFAPC-1, compared with that in the normal pancreatic epithelial cell line HPC-Y5. Overexpression of PREX2 significantly promoted the proliferation, invasion and migration of pancreatic cancer PANC-1 cells, while small interfering RNA-induced knockdown of PREX2 expression significantly inhibited the proliferation, invasion and migration of these cells. Investigation of the molecular mechanism revealed that the overexpression of PREX2 upregulated the phosphorylation levels of PTEN, indicating that the activity of PTEN was reduced, which further increased the phosphorylation levels of AKT, which indicated that the activity of the PI3K signaling pathway was upregulated. By contrast, knockdown of PREX2 upregulated the activity of PTEN and inhibited the activity of the PI3K signaling pathway. In conclusion, the present study demonstrated that PREX2 regulates the proliferation, invasion and migration of pancreatic cancer cells, probably at least via modulation of the activity of PTEN and the PI3K signaling pathway.

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Section: Promoting Role Of Prex2 In Pancreatic Cancer Cell Migrationmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway

et al. 2016

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“…in the brain, which express P-Rex1 but no GPCR-dependent PI3K), concomitant activation of GPCRs with another class of receptor that couples to protein-tyrosine kinase-regulated PI3K could provide the required P-Rex1 translocation and activation signals. Equally, it seems likely that similar coincidence detection applies to membrane recruitment and activation of the other members of the P-Rex family, P-Rex2 and P-Rex2b (4,5), that are not expressed in hemopoietic cells.…”

Section: Discussionmentioning

confidence: 99%

Membrane Translocation of P-Rex1 Is Mediated by G Protein βγ Subunits and Phosphoinositide 3-Kinase

Barber

Donald

Thelen

et al. 2007

Journal of Biological Chemistry

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P-Rex1 is a guanine-nucleotide exchange factor (GEF) for the small GTPase Rac that is directly activated by the ␤␥ subunits of heterotrimeric G proteins and by the lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP 3 ), which is generated by phosphoinositide 3-kinase (PI3K). G␤␥ subunits and PIP 3 are membrane-bound, whereas the intracellular localization of P-Rex1 in basal cells is cytosolic. Activation of PI3K alone is not sufficient to promote significant membrane translocation of P-Rex1. Here we investigated the subcellular localization of P-Rex1 by fractionation of Sf9 cells co-expressing P-Rex1 with G␤␥ and/or PI3K. In basal, serum-starved cells, P-Rex1 was mainly cytosolic, but 7% of the total was present in the 117,000 ؋ g membrane fraction. Co-expression of P-Rex1 with either G␤␥ or PI3K caused only an insignificant increase in P-Rex1 membrane localization, whereas G␤␥ and PI3K together synergistically caused a robust increase in membrane-localized P-Rex1 to 23% of the total. PI3K-driven P-Rex1 membrane recruitment was wortmannin-sensitive. The use of P-Rex1 mutants showed that the isolated Dbl homology/pleckstrin homology domain tandem of P-Rex1 is sufficient for synergistic G␤␥-and PI3K-driven membrane localization; that the enzymatic GEF activity of P-Rex1 is not required for membrane translocation; and that the other domains of P-Rex1 (DEP, PDZ, and IP4P) contribute to keeping the enzyme localized in the cytosol of basal cells. In vitro Rac2-GEF activity assays showed that membrane-derived purified P-Rex1 has a higher basal activity than cytosol-derived P-Rex1, but both can be further activated by PIP 3 and G␤␥ subunits.The small GTPase Rac (isoforms Rac1, Rac2, and Rac3) is a member of the Rho family of GTPases that regulates a range of important cellular functions, including gene expression, cytoskeletal structure, and reactive oxygen species formation (1). Like all small GTPases, Rac is directly activated by guaninenucleotide exchange factors (GEFs) 3 (2). The P-Rex family of Rac-GEFs is composed of P-Rex1, P-Rex2, and P-Rex2b (3-5). P-Rex1 is expressed in white blood cells and brain (3), P-Rex2 expression is more widespread but low or absent in leukocytes (4), and P-Rex2b, a splice variant of P-Rex2 that lacks the C-terminal half, is expressed mainly in the heart (5). Studies in P-Rex1-deficient mice have shown that P-Rex1 is involved in the regulation of G protein-coupled receptor (GPCR)-dependent Rac2 activation in neutrophils, production of reactive oxygen species, chemotaxis, and neutrophil recruitment to inflammatory sites (6, 7). In the neuronal PC12 cell line, RNA interference-mediated down-regulation of P-Rex1 leads to impaired neurotrophin-stimulated cell migration (8). In the endothelial HUVEC cell line, suppression of P-Rex2b levels by RNA interference results in reduced Rac1 activation and cell migration in response to sphingosine 1-phosphate (9). P-Rex family GEFs are directly and synergistically activated in vitro and in vivo by the ␤␥ subunits of heterotrimeric...

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“…As phosphatidylinositol 3-kinase has been reported to regulate Rac1 activity through the several guanine nucleotide exchange factors, such as SWAP70 and P-REX2 downstream of Gab1 (53)(54)(55), and Vav and Tiam-1 are also known to mediate Rac1 activity involved in transformation (56, 57), we initially speculated that the implication of Crk in HGF-mediated Rac1 activation may be partial. However, the significant suppression of HGF-dependent activation of Rac1, cell motility, and scattering was shown in Crk knockdown cells, which may suggest the crucial role for Crk in HGF-evoked activation of Rac1 and following cell motility in human synovial sarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

Adaptor Molecule Crk Is Required for Sustained Phosphorylation of Grb2-Associated Binder 1 and Hepatocyte Growth Factor–Induced Cell Motility of Human Synovial Sarcoma Cell Lines

Watanabe

Tsuda

Makino

et al. 2006

Molecular Cancer Research

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Activation of the c-Met receptor tyrosine kinase through its ligand, hepatocyte growth factor (HGF), promotes mitogenic, motogenic, and morphogenic cellular responses. Aberrant HGF/c-Met signaling has been strongly implicated in tumor cell invasion and metastasis. Both HGF and its receptor c-Met have been shown to be overexpressed in human synovial sarcoma, which often metastasizes to the lung; however, little is known about HGF-mediated biological effects in this sarcoma. Here, we provide evidence that Crk adaptor protein is required for the sustained phosphorylation of c-Met-docking protein Grb2-associated binder 1 (Gab1) in response to HGF, leading to the enhanced cell motility of human synovial sarcoma cell lines SYO-1, HS-SY-II, and Fuji. HGF stimulation induced the sustained phosphorylation on Y307 of Gab1 where Crk was recruited. Crk knockdown by RNA interference disturbed this HGF-induced tyrosine phosphorylation of Gab1. By mutational analysis, we identified that Src homology 2 domain of Crk is indispensable for the induction of the phosphorylation on multiple Tyr-X-X-Pro motifs containing Y307 in Gab1. HGF remarkably stimulated cell motility and scattering of synovial sarcoma cell lines, consistent with the prominent activation of Rac1, extreme filopodia formation, and membrane ruffling.

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P‐REX2, a novel PI‐3‐kinase sensitive Rac exchange factor

Cited by 90 publications

References 16 publications

PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway

PREX2 promotes the proliferation, invasion and migration of pancreatic cancer cells by modulating the PI3K signaling pathway

Membrane Translocation of P-Rex1 Is Mediated by G Protein βγ Subunits and Phosphoinositide 3-Kinase

Adaptor Molecule Crk Is Required for Sustained Phosphorylation of Grb2-Associated Binder 1 and Hepatocyte Growth Factor–Induced Cell Motility of Human Synovial Sarcoma Cell Lines

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