Rapid Remodeling of Invadosomes by Gi-coupled Receptors

Kedziora, Katarzyna M.; Leyton-Puig, Daniela; Argenzio, Elisabetta; Boumeester, Anja J.; Butselaar, Bram van; Yin, Taofei; Wu, Yi; Leeuwen, Frank N. van; Innocenti, Metello; Jalink, Kees; Moolenaar, Wouter H.

doi:10.1074/jbc.m115.695940

Cited by 41 publications

(55 citation statements)

References 60 publications

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“…This activation is dependent on the transactivation of the EGFR. The proposed signaling pathway, based on our findings and on existing literature (Buchanan et al, 2006; Kedziora et al, 2016), mediating the effect of EP4 on invadopodia maturation is depicted in Figure 5. Furthermore, we have shown that PGE 2 , or specific EP4 stimulation with CAY10598, can promote invadopodia in the absence of EGF.…”

Section: Discussionmentioning

confidence: 66%

EP4 receptor promotes invadopodia and invasion in human breast cancer

Tönisen

Perrin

Bayarmagnai

et al. 2017

European Journal of Cell Biology

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The production of Prostaglandin E2 (PGE2) is elevated in human breast cancer cells. The abnormal expression of COX-2, which is involved in the synthesis of PGE2, was recently reported as a critical determinant for invasiveness of human breast cancer cells. Autocrine and paracrine PGE2-mediated stimulation of the PGE2 receptor EP4 transduces multiple signaling pathways leading to diverse patho-physiological effects, including tumor cell invasion and metastasis. It is known that PGE2-induced EP4 activation can transactivate the intracellular signaling pathway of the epidermal growth factor receptor (EGFR). In malignant cancer cells, EGFR pathway activation promotes invadopodia protrusions, which further leads to degradation of the surrounding extracellular matrix (ECM). Despite the known influence of EP4 on the EGFR signaling pathway, the effect of EP4 stimulation on invadopodia formation in human breast cancer was never tested directly. Here we demonstrate the involvement of EP4 in invasion and its effect on invadopodia in breast cancer MDA-MB-231 cells using 2D invadopodia and 3D invasion in vitro assays as well as intravital microscopy. The results show that stimulation with the selective EP4 agonist CAY10598 or PGE2 promotes invadopodia-mediated degradation of the ECM, as well as the invasion of breast cancer cells in in vitro models. The effect on matrix degradation can be abrogated via direct inhibition of EP4 signaling as well as via inhibition of EGFR tyrosine kinase, indicating that EP4-mediated effects on invadopodia-driven degradation are EGFR dependent. Finally, using xenograft mouse models, we show that short-term systemic treatment with CAY10598 results in a >9-fold increase in the number of invadopodia. These findings highlight the importance of further investigation on the role of EP4-EGFR crosstalk in invadopodia formation.

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Section: Discussionmentioning

confidence: 66%

EP4 receptor promotes invadopodia and invasion in human breast cancer

Tönisen

Perrin

Bayarmagnai

et al. 2017

European Journal of Cell Biology

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“…Moreover, we show that constitutively activated G αi protiens are sufficient to mediate HER2 and Src phosphorylation and this phosphorylation may contribute to cellular invasion of PC cells, suggesting that CXCR4 activated G αi proteins are sufficient for PC cell invasion. Recent studies support the role of G αi proteins in Src induced formation of invadosomes, which are cellular protrusions exhibited in migrating/invading cells, where a transient activation of Cdc42 is implicated downstream of GPCR activation [40]; thus, we cannot rule out the role of Cdc42 downstream of CXCR4 activated Src activation in PC cells.…”

Section: Discussionmentioning

confidence: 81%

Pharmacological targeting of CXCL12/CXCR4 signaling in prostate cancer bone metastasis

et al. 2016

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BackgroundThe CXCL12/CXCR4 axis transactivates HER2 and promotes intraosseous tumor growth. To further explore the transactivation of HER2 by CXCL12, we investigated the role of small GTP protein Gαi2 in Src and HER2 phosphorylation in lipid raft membrane microdomains and the significance of CXCR4 in prostate cancer bone tumor growth.MethodsWe used a variety of methods such as lipid raft isolation, invasion assays, an in vivo model of intratibial tumor growth, bone histomorphometry, and immunohistochemistry to determine the role of CXCR4 signaling in lipid raft membrane microdomains and effects of targeting of CXCR4 for bone tumor growth.ResultsWe determined that (a) CXCL12/CXCR4 transactivation of EGFR and HER2 is confined to lipid raft membrane microdomains, (b) CXCL12 activation of HER2 and Src is mediated by small GTP proteins in lipid rafts, (c) inhibition of the CXCL12/CXCR4 axis through plerixafor abrogates the initial establishment of tumor growth without affecting the growth of established bone tumors, and (d) inhibition of EGFR signaling through gefitinib leads to inhibition of established bone tumor growth.ConclusionsThese data suggest that lipid raft membrane microdomains are key sites for CXCL12/CXCR4 transactivation of HER2 via small GTP binding protein Gαi2 and Src kinase. The initial establishment of prostate cancer is supported by the endosteal niche, and blocking the CXCL12/CXCR4 axis of this niche along with its downstream signaling severely compromises initial establishment of tumors in the bone microenvironment, whereas expanding bone tumors are sensitive only to the members of growth factor receptor inhibition.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0552-0) contains supplementary material, which is available to authorized users.

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“…Independent from these studies, TRPC6 channels are associated with G protein agonists, smooth muscle contraction, and positively correlated with hypertension [46]. Although ROCK is commonly associated with G 12/13 [47, 48], there is evidence in vascular endothelial cells that supports a link between G i and ROCK [49]. Taken together, it is possible that chemerin-induced contraction could be mediated through ROCK activation of non-voltage dependent ion channels, like TRPC6.…”

Section: Discussionmentioning

confidence: 99%

Chemerin-induced arterial contraction is Gi- and calcium-dependent

Ferland

Darios

Neubig

et al. 2017

Vascular Pharmacology

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Chemerin is an adipokine associated with increased blood pressure, and may link obesity with hypertension. We tested the hypothesis that chemerin-induced contraction of the vasculature occurs via calcium flux in smooth muscle cells. Isometric contraction of rat aortic rings was performed in parallel with calcium kinetics of rat aortic smooth muscle cells to assess the possible signaling pathway. Chemerin-9 (nonapeptide of the chemerin S157 isoform) caused a concentration-dependent contraction of isolated aorta (EC50 100 nM) and elicited a concentration-dependent intracellular calcium response (EC50 10 nM). Pertussis toxin (Gi inhibitor), verapamil (L-type Ca2+ channel inhibitor), PP1 (Src inhibitor), and Y27632 (Rho kinase inhibitor) reduced both calcium influx and isometric contraction to chemerin-9 but PD098059 (Erk MAPK inhibitor) and U73122 (PLC inhibitor) had little to no effect on either measure of chemerin signaling. Although our primary aim was to examine chemerin signaling, we also highlight differences in the mechanisms of chemerin-9 and recombinant chemerin S157. These data support a chemerin-induced contractile mechanism in vascular smooth muscle that functions through Gi proteins to activate L-type Ca2+ channels, Src, and Rho kinase. There is mounting evidence linking chemerin to hypertension and this mechanism brings us closer to targeting chemerin as a form of therapy.

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Rapid Remodeling of Invadosomes by Gi-coupled Receptors

Cited by 41 publications

References 60 publications

EP4 receptor promotes invadopodia and invasion in human breast cancer

EP4 receptor promotes invadopodia and invasion in human breast cancer

Pharmacological targeting of CXCL12/CXCR4 signaling in prostate cancer bone metastasis

Chemerin-induced arterial contraction is Gi- and calcium-dependent

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