Gastrin-stimulated Gα13 Activation of Rgnef Protein (ArhGEF28) in DLD-1 Colon Carcinoma Cells

Masià-Balagué, Míriam; Izquierdo, Ismael; Garrido, Georgina; Cordomí, Arnau; Pérez‐Benito, Laura; Miller, Nichol L.G.; Schlaepfer, David D.; Gigoux, Véronique; Aragay, Anna M.

doi:10.1074/jbc.m114.628164

Cited by 23 publications

(18 citation statements)

References 64 publications

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“…The list of GPCR-regulated RhoGEFs is based on studies showing, at least by coimunoprecipitation or other equivalent assays, interaction between the indicated G proteins and RhoGEFs. Ga 12/13 -regulated RhoGEFs: p115RhoGEF/ARHGEF1 (Hart et al, 1998), LARG/ARHGEF12 (Fukuhara et al, 2000), PDZ-RhoGEF/ARHGEF11 (Fukuhara et al, 1999), MCF2/Dbl/ARHGEF21 (Jin and Exton, 2000), ARHGEF2/GEF-H1 (Meiri et al, 2014), and ARHGEF28/RGNEF (Masià-Balagué et al, 2015). Ga q -regulated RhoGEFs: p63RhoGEF/ARHGEF25 (Lutz et al, 2005(Lutz et al, , 2007, TRIO/ARHGEF23 (Rojas et al, 2007;Vaqué et al, 2013), and ARHGEF28/RGNEF (Masià-Balagué et al, 2015).…”

Section: Protumoral Chemotactic Agonistsmentioning

confidence: 99%

“…Ga 12/13 -regulated RhoGEFs: p115RhoGEF/ARHGEF1 (Hart et al, 1998), LARG/ARHGEF12 (Fukuhara et al, 2000), PDZ-RhoGEF/ARHGEF11 (Fukuhara et al, 1999), MCF2/Dbl/ARHGEF21 (Jin and Exton, 2000), ARHGEF2/GEF-H1 (Meiri et al, 2014), and ARHGEF28/RGNEF (Masià-Balagué et al, 2015). Ga q -regulated RhoGEFs: p63RhoGEF/ARHGEF25 (Lutz et al, 2005(Lutz et al, , 2007, TRIO/ARHGEF23 (Rojas et al, 2007;Vaqué et al, 2013), and ARHGEF28/RGNEF (Masià-Balagué et al, 2015). Gbg-regulated RhoGEFs: P-Rex1 (Welch et al, 2002) and P-Rex2 (Donald et al, 2004), PLEKHG2 (Ueda et al, 2008), p114RhoGEF/ARHGEF18 (Niu et al, 2003), ARHGEF5/TIM (Wang et al, 2009), and MCF2/Dbl/ARHGEF21 (Nishida et al, 1999).…”

Section: Protumoral Chemotactic Agonistsmentioning

confidence: 99%

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Gβγ Pathways in Cell Polarity and Migration Linked to Oncogenic GPCR Signaling: Potential Relevance in Tumor Microenvironment

et al. 2016

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Cancer cells and stroma cells in tumors secrete chemotactic agonists that exacerbate invasive behavior, promote tumor-induced angiogenesis, and recruit protumoral bone marrow-derived cells. In response to shallow gradients of chemotactic stimuli recognized by G protein-coupled receptors (GPCRs), Gβγ-dependent signaling cascades contribute to specifying the spatiotemporal assembly of cytoskeletal structures that can dynamically alter cell morphology. This sophisticated process is intrinsically linked to the activation of Rho GTPases and their cytoskeletal-remodeling effectors. Thus, Rho guanine nucleotide exchange factors, the activators of these molecular switches, and their upstream signaling partners are considered participants of tumor progression. Specifically, phosphoinositide-3 kinases (class I PI3Ks, β and γ) and P-Rex1, a Rac-specific guanine nucleotide exchange factor, are fundamental Gβγ effectors in the pathways controlling directionally persistent motility. In addition, GPCR-dependent chemotactic responses often involve endosomal trafficking of signaling proteins; coincidently, endosomes serve as signaling platforms for Gβγ In preclinical murine models of cancer, inhibition of Gβγ attenuates tumor growth, whereas in cancer patients, aberrant overexpression of chemotactic Gβγ effectors and recently identified mutations in Gβ correlate with poor clinical outcome. Here we discuss emerging paradigms of Gβγ signaling in cancer, which are essential for chemotactic cell migration and represent novel opportunities to develop pathway-specific pharmacologic treatments.

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Section: Protumoral Chemotactic Agonistsmentioning

confidence: 99%

Section: Protumoral Chemotactic Agonistsmentioning

confidence: 99%

Gβγ Pathways in Cell Polarity and Migration Linked to Oncogenic GPCR Signaling: Potential Relevance in Tumor Microenvironment

et al. 2016

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“…In sharp contrast to the preferential Gα12 binding we observed for AKAP-Lbc and p114RhoGEF, Rgnef shows functional interaction with Gα13 but not Gα12 [42]. These findings suggest a G12/13-responsive domain existed in a common ancestor of AKAP-Lbc, p114RhoGEF, and Rgnef, and after the gene duplication event that produced Gα12 and Gα13, the Rgnef lineage evolved selectivity for Gα13 while the lineage that yielded AKAP-Lbc and p114RhoGEF was tuned to become specialized for Gα12 interaction.…”

Section: Discussionmentioning

confidence: 86%

A Gα12-specific Binding Domain in AKAP-Lbc and p114RhoGEF

Martin¹,

Cavagnini²,

Brawley³

et al. 2016

Journal of Molecular Signaling

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AKAP-Lbc is a Rho-activating guanine nucleotide exchange factor (RhoGEF) important in heart development and pro-fibrotic signaling in cardiomyocytes. Heterotrimeric G proteins of the G12/13 subfamily, comprising Gα12 and Gα13, are well characterized as stimulating a specialized group of RhoGEFs through interaction with their RGS-homology (RH) domain. Despite lacking an RH domain, AKAP-Lbc is bound by Gα12 through an unknown mechanism to activate Rho signaling. We identified a Gα12-binding region near the C-terminus of AKAP-Lbc, closely homologous to a region of p114RhoGEF that we also discovered to interact with Gα12. This binding mechanism is distinct from the well-studied interface between RH-RhoGEFs and G12/13 α subunits, as demonstrated by Gα12 mutants selectively impaired in binding either this AKAP-Lbc/p114RhoGEF region or RH-RhoGEFs. AKAP-Lbc and p114RhoGEF showed high specificity for binding Gα12 in comparison to Gα13, and experiments using chimeric G12/13 α subunits mapped determinants of this selectivity to the N-terminal region of Gα12. In cultured cells expressing constitutively GDP-bound Gα12 or Gα13, the Gα12 construct was more potent in exerting a dominant-negative effect on serum-mediated signaling to p114RhoGEF, demonstrating coupling of these signaling proteins in a cellular pathway. In addition, charge-reversal of conserved residues in AKAP-Lbc and p114RhoGEF disrupted Gα12 binding for both proteins, suggesting they harbor a common structural mechanism for interaction with this α subunit. Our results provide the first evidence of p114RhoGEF as a Gα12 signaling effector, and define a novel region conserved between AKAP-Lbc and p114RhoGEF that allows Gα12 signaling input to these non-RH RhoGEFs.

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“…Cholecystokinin B receptor (CCKBR), a member of the family of G protein-coupled receptors (GPCR), couples with gastrin and cholecystokinin, which are principally expressed in the gastrointestinal tract 9 . CCKBR was first regarded as a regulator of gastric acid secretion and the calcium signaling pathway, and now CCKBR has been identified and characterized as a stimulator in multiple malignancies, including pancreatic cancer 9 - 11 . Compared with normal tissues, the expression level of CCKBR is significantly increased in pancreatic cancerous tissues 12 .…”

Section: Introductionmentioning

confidence: 99%

“…Compared with normal tissues, the expression level of CCKBR is significantly increased in pancreatic cancerous tissues 12 . The human pancreas produces gastrin during fetal development, and no gastrin is expressed in the healthy adult pancreas; however, gastrin is reexpressed in pancreatic cancerous tissues, where it enhances proliferation and migration through an autocrine mechanism 11 , 13 . However, the role of CCKBR in pancreatic cancer metastasis still remains to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Gastrin stimulates pancreatic cancer cell directional migration by activating the Gα12/13–RhoA–ROCK signaling pathway

Ding

et al. 2018

Exp Mol Med

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The mechanism by which gastrin promotes pancreatic cancer cell metastasis is unclear. The process of directing polarized cancer cells toward the extracellular matrix is principally required for invasion and distant metastasis; however, whether gastrin can induce this process and its underlying mechanism remain to be elucidated. In this study, we found that gastrin-induced phosphorylation of paxillin at tyrosine 31/118 and RhoA activation as well as promoted the metastasis of PANC-1 cancer cells. Depletion of Gα12 and Gα13 inhibited the phosphorylation of paxillin and downstream activation of GTP-RhoA, blocked the formation and aggregation of focal adhesions and facilitated polarization of actin filaments induced by gastrin. Suppression of RhoA and ROCK also exhibited identical results. Selective inhibition of the CCKBR–Gα12/13–RhoA–ROCK signaling pathway blocked the reoriented localization of the Golgi apparatus at the leading edge of migrated cancer cells. YM022 and Y-27632 significantly suppressed hepatic metastasis of orthotic pancreatic tumors induced by gastrin in vivo. Collectively, we demonstrate that gastrin promotes Golgi reorientation and directional polarization of pancreatic cancer cells by activation of paxillin via the CCKBR–Gα12/13–RhoA–ROCK signal pathway.

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Gastrin-stimulated Gα13 Activation of Rgnef Protein (ArhGEF28) in DLD-1 Colon Carcinoma Cells

Cited by 23 publications

References 64 publications

Gβγ Pathways in Cell Polarity and Migration Linked to Oncogenic GPCR Signaling: Potential Relevance in Tumor Microenvironment

Gβγ Pathways in Cell Polarity and Migration Linked to Oncogenic GPCR Signaling: Potential Relevance in Tumor Microenvironment

A Gα12-specific Binding Domain in AKAP-Lbc and p114RhoGEF

Gastrin stimulates pancreatic cancer cell directional migration by activating the Gα12/13–RhoA–ROCK signaling pathway

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