Rho GTPases modulate malignant transformation of tumor cells

Orgaz, José L.; Herráiz, Cecilia; Sanz-Moreno, Victoria

doi:10.4161/sgtp.29019

Cited by 146 publications

(164 citation statements)

References 238 publications

(250 reference statements)

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“…Note that we cannot completely rule out that potential mutations in Rac1 and Cdc42 could also impact their activity in human PCC. Indeed, several recent studies reported point mutations in Rho-GTPases as driver mutations in various types of cancer, including melanoma, lymphoma, breast, lung, and head and neck cancers (for review see Alan &Lundquist 2013 andOrgaz et al 2014). However, none of these studies reported mutations leading to inactivation of the Rac1 or Cdc42 GTPase.…”

Section: :4mentioning

confidence: 99%

“…Consequently, Rho GTPases have been largely implicated in many types of cancer, and numerous studies have shown that aberrant expression of Rho GTPases is associated with tumor growth, invasion, and metastasis. The evidence for the role of Rho GTPases in various stages of tumorigenesis has been compiled in comprehensive reviews (Ellenbroek & Collard 2007, Grise et al 2009, Karlsson et al 2009, Parri & Chiarugi 2010, Alan & Lundquist 2013, Orgaz et al 2014). However, the expression level of Rho GTPase genes or proteins does not necessarily reflect their activation state.…”

Section: Introductionmentioning

confidence: 99%

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Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression

Croisé¹,

Houy²,

Gand³

et al. 2016

Endocrine-Related Cancer

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Among small GTPases from the Rho family, Cdc42, Rac, and Rho are well known to mediate a large variety of cellular processes linked with cancer biology through their ability to cycle between an inactive (GDP-bound) and an active (GTP-bound) state. Guanine nucleotide exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate the activated form, whereas the GTPase-activating proteins (GAPs) catalyze GTP hydrolysis, leading to the inactivated form. Modulation of Rho GTPase activity following altered expression of Rho-GEFs and/or Rho-GAPs has already been reported in various human tumors. However, nothing is known about the Rho GTPase activity or the expression of their regulators in human pheochromocytomas, a neuroendocrine tumor (NET) arising from chromaffin cells of the adrenal medulla. In this study, we demonstrate, through an ELISA-based activity assay, that Rac1 and Cdc42 activities decrease in human pheochromocytomas (PCCs) compared with the matched adjacent non-tumor tissue. Furthermore, through quantitative mass spectrometry (MS) approaches, we show that the expression of two Rho-GEF proteins, namely ARHGEF1 and FARP1, is significantly reduced in tumors compared with matched non-tumor tissue, whereas ARHGAP36 expression is increased. Moreover, siRNA-based knockdown of ARHGEF1 and FARP1 in PC12 cells leads to a significant inhibition of Rac1 and Cdc42 activities, respectively. Finally, a principal component analysis (PCA) of our dataset was able to discriminate PCC from non-tumor tissue and indicates a close correlation between Cdc42/Rac1 activity and FARP1/ARHGEF1 expression. Altogether, our findings reveal for the first time the importance of modulation of Rho GTPase activities and expression of their regulators in human PCCs. 23:4Research 281-293 P Croisé et al.Rho-GTPase activity in human pheochromocytoma

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Section: :4mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression

Croisé¹,

Houy²,

Gand³

et al. 2016

Endocrine-Related Cancer

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“…[2][3][4][5] Therefore, Rho GTPase signaling has been involved in many aspects of cancer biology, from tumor initiation to tumor cell proliferation, invasion and metastasis. 6,7 How Rho GTPases are modulated in tumor is currently a major and a challenging issue. Most studies have monitored the expression levels of Rho GTPases in human cancer and several of them have been found overexpressed.…”

mentioning

confidence: 99%

Inhibition of Cdc42 and Rac1 activities in pheochromocytoma, the adrenal medulla tumor

et al. 2016

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Altered Rho GTPase signaling has been linked to many types of cancer. As many small G proteins, Rho GTPases cycle between an active and inactive state thanks to specific regulators that catalyze exchange of GDP into GTP (Rho-GEF) or hydrolysis of GTP into GDP (Rho-GAP). Recent studies have shown that alteration takes place either at the level of Rho proteins themselves (expression levels, point mutations) or at the level of their regulators, mostly RhoGEFs and RhoGAPs. Most reports describe Rho GTPases gain of function that may participate to the tumorigenesis processes. In contrast, we have recently reported that decreased activities of Cdc42 and Rac1 as well as decreased expression of 2 Rho-GEFs, FARP1 and ARHGEF1, correlate with pheochromocytomas, a tumor developing in the medulla of the adrenal gland (Croise et al., Endocrine Related Cancer, 2016). Here we highlight the major evidence and further study the correlation between Rho GTPases activities and expression levels of ARHGEF1 and FARP1. Finally we also discuss how the decrease of Cdc42 and Rac1 activities may help human pheochromocytomas to develop and comment the possible relationship between FARP1, ARHGEF1 and the 2 Rho GTPases Cdc42 and Rac1 in tumorigenesis.

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“…The Rac proteins (Rac1, Rac2, and Rac3) are a subgroup of the Rho-GTPase family that regulate cell motility and, when deregulated, drive cancer invasion and metastasis (1)(2)(3). Rac proteins undergo rapid and spatiotemporally coordinated cycles of activation and inactivation linked to upstream receptor signaling by guanine nucleotide exchange factors (GEFs) 2 (4).…”

Section: Waf1/cip1mentioning

confidence: 99%

“…relative to control shRNA, which was assigned an arbitrary value of 1 (n ϭ 3). C, quantitative RT-PCR analysis of PREX1 mRNA normalized to GAPDH from MCF-7-luc-F5 cells stably expressing control shRNA, PREX1 shRNA (1), or PREX1 shRNA (2). Data are presented as mean -fold difference Ϯ S.E.…”

Section: Prex1 Regulates Cell Proliferation and Cyclin D1 And P21mentioning

confidence: 99%

PtdIns(3,4,5)P3-dependent Rac Exchanger 1 (PREX1) Rac-Guanine Nucleotide Exchange Factor (GEF) Activity Promotes Breast Cancer Cell Proliferation and Tumor Growth via Activation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Signaling

Liu

Ooms

Srijakotre

et al. 2016

Journal of Biological Chemistry

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PtdIns(3,4,5)P 3 -dependent Rac exchanger 1 (PREX1) is a Racguanine nucleotide exchange factor (GEF) overexpressed in a significant proportion of human breast cancers that integrates signals from upstream ErbB2/3 and CXCR4 membrane surface receptors. However, the PREX1 domains that facilitate its oncogenic activity and downstream signaling are not completely understood. We identify that ERK1/2 MAPK acts downstream of PREX1 and contributes to PREX1-mediated anchorage-independent cell growth. PREX1 overexpression increased but its shRNA knockdown decreased ERK1/2 phosphorylation in response to EGF/IGF-1 stimulation, resulting in induction of the cell cycle regulators cyclin D1 and p21 WAF1/CIP1. PREX1-mediated ERK1/2 phosphorylation, anchorage-independent cell growth, and cell migration were suppressed by inhibition of MEK1/2/ERK1/2 signaling. PREX1 overexpression reduced staurosporine-induced apoptosis whereas its shRNA knockdown promoted apoptosis in response to staurosporine or the anti-estrogen drug tamoxifen. Expression of wild-type but not GEF-inactive PREX1 increased anchorage-independent cell growth. In addition, mouse xenograft studies revealed that expression of wild-type but not GEF-dead PREX1 resulted in the formation of larger tumors that displayed increased phosphorylation of ERK1/2 but not AKT. The impaired anchorage-independent cell growth, apoptosis, and ERK1/2 signaling observed in stable PREX1 knockdown cells was restored by expression of wild-type but not GEF-dead-PREX1. Therefore, PREX1-Rac-GEF activity is critical for PREX1-dependent anchorage-independent cell growth and xenograft tumor growth and may represent a possible therapeutic target for breast cancers that exhibit PREX1 overexpression.The Rac proteins (Rac1, Rac2, and Rac3) are a subgroup of the Rho-GTPase family that regulate cell motility and, when deregulated, drive cancer invasion and metastasis (1-3). Rac proteins undergo rapid and spatiotemporally coordinated cycles of activation and inactivation linked to upstream receptor signaling by guanine nucleotide exchange factors (GEFs) 2 (4). The most common mechanism for Rac hyperactivation in human cancer is via dysregulation of Rac-GEF activity. PtdIns (3,4,5)P 3 -dependent Rac exchanger 1 (PREX1) is a member of the Dbl family of Rho-GEFs that promotes chemoattractantstimulated neutrophil chemotaxis and reactive O 2 species formation (5-7). PREX1 is a multidomain protein that contains an N-terminal catalytic Dbl-homologous (DH) domain, which activates Rac, adjacent to a pleckstrin homology (PH) domain, which binds to and is activated by PI3K-generated PtdIns(3,4,5)P 3 , followed by two dishevelled, EGL-10 and pleckstrin (DEP) domains, two PDZ domains, and a catalytically inactive C-terminal inositol polyphosphate 4-phosphatase (IP4P) domain, which shares 30% amino acid identity with the catalytically active IP4P domain of the inositol polyphosphate 4-phosphatases INPP4A and INPP4B (5,8,9). The IP4P domain of PREX1 contains a common catalytic CX 5 R motif shared by dual specificity p...

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Rho GTPases modulate malignant transformation of tumor cells

Cited by 146 publications

References 238 publications

Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression

Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression

Inhibition of Cdc42 and Rac1 activities in pheochromocytoma, the adrenal medulla tumor

PtdIns(3,4,5)P3-dependent Rac Exchanger 1 (PREX1) Rac-Guanine Nucleotide Exchange Factor (GEF) Activity Promotes Breast Cancer Cell Proliferation and Tumor Growth via Activation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Signaling

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