Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b

Schnelzer, Andreas; Prechtel, Dieter; Knaus, Ulla G.; Dehne, Kerstin; Gerhard, Markus; Graeff, H.; Harbeck, Nadia; Schmitt, Manfred; Lengyel, Ernst

doi:10.1038/sj.onc.1203621

Cited by 373 publications

(358 citation statements)

References 32 publications

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“…Additionally, we also show that EHT 1864 binds closely related Rac isoforms, Rac2 and Rac1b, and with a lower affinity, Rac3. The activity against Rac1b is important in light of the fact that this splice variant is constitutively activated and transforming and preferentially expressed in breast and colon cancers (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…The Rac branch of the Rho family is composed of three closely related proteins, Rac1, Rac2, and Rac3, that share significant sequence (85%) and biochemical identity (51). Additionally, an alternative splice variant of Rac1, Rac1b, has been found to be expressed in human cancer cells (17,18). Rac1b contains a 19-residue insert sequence upstream of the switch 2 region of Rac1, which perturbs interaction with regulator proteins and effectors and displays biological properties of a constitutively activated, transforming protein (19).…”

Section: Eht 1864 Specifically Inhibits Pdgf-induced Lamellipodiamentioning

confidence: 99%

“…Rac is essential for transformation caused by Ras and other oncogenes (11)(12)(13)(14)(15)(16). The Rac1b splice variant of Rac1 is constitutively active and transforming and found overexpressed in breast and colon cancers (17)(18)(19). Mutation and overexpression of Rac3 was seen in human brain tumors, and RNA interference demonstrated a role for Rac1 and Rac3 in human glioblastoma invasion (20,21).…”

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confidence: 99%

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Specificity and Mechanism of Action of EHT 1864, a Novel Small Molecule Inhibitor of Rac Family Small GTPases

Shutes

Onesto

Picard

et al. 2007

Journal of Biological Chemistry

289

263

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There is now considerable experimental evidence that aberrant activation of Rho family small GTPases promotes the uncontrolled proliferation, invasion, and metastatic properties of human cancer cells. Therefore, there is considerable interest in the development of small molecule inhibitors of Rho GTPase function. However, to date, most efforts have focused on inhibitors that indirectly block Rho GTPase function, by targeting either enzymes involved in post-translational processing or downstream protein kinase effectors. We recently determined that the EHT 1864 small molecule can inhibit Rac function in vivo. In this study, we evaluated the biological and biochemical specificities and biochemical mechanism of action of EHT 1864. We determined that EHT 1864 specifically inhibited Rac1-dependent platelet-derived growth factor-induced lamellipodia formation. Furthermore, our biochemical analyses with recombinant Rac proteins found that EHT 1864 possesses high affinity binding to Rac1, as well as the related Rac1b, Rac2, and Rac3 isoforms, and this association promoted the loss of bound nucleotide, inhibiting both guanine nucleotide association and Tiam1 Rac guanine nucleotide exchange factor-stimulated exchange factor activity in vitro. EHT 1864 therefore places Rac in an inert and inactive state, preventing its engagement with downstream effectors. Finally, we evaluated the ability of EHT 1864 to block Rac-dependent growth transformation, and we determined that EHT 1864 potently blocked transformation caused by constitutively activated Rac1, as well as Rac-dependent transformation caused by Tiam1 or Ras. Taken together, our results suggest that EHT 1864 selectively inhibits Rac downstream signaling and transformation by a novel mechanism involving guanine nucleotide displacement.Rho family proteins (20 human members) comprise a major branch of the Ras superfamily of small GTPases (1, 2). Like Ras, Rho GTPases function as GDP/GTP-regulated binary on-off switches. In resting, quiescent cells, Rho GTPases exist predominately in their inactive, GDP-bound state. Upon growth factor stimulation, Rho-specific guanine nucleotide exchange factors (RhoGEFs) 4 are activated, and they stimulate the intrinsic guanine nucleotide exchange activity to promote formation of the active GTP-bound protein. Rho-GTP binds preferentially to downstream effector proteins. Rho-specific GTPaseactivating proteins then stimulate the intrinsic GTP hydrolysis activity of Rho GTPases, returning the protein to its inactive state and terminating effector interaction.RhoA, Rac1, and Cdc42 are the best studied and understood members of the Rho GTPase family (1, 2). Rho GTPases are regulators of a diverse variety of cellular processes that include regulation of cell proliferation, actin cytoskeleton reorganization, and gene expression (3). Like Ras and other members of the Ras superfamily (4, 5), the aberrant activity of Rho GTPases has been implicated in cancer and other human diseases (6 -10). In particular, the Rac subfamily has also been linked to c...

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Section: Discussionmentioning

confidence: 99%

Section: Eht 1864 Specifically Inhibits Pdgf-induced Lamellipodiamentioning

confidence: 99%

mentioning

confidence: 99%

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Specificity and Mechanism of Action of EHT 1864, a Novel Small Molecule Inhibitor of Rac Family Small GTPases

Shutes

Onesto

Picard

et al. 2007

Journal of Biological Chemistry

289

263

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“…9 In breast cancer, Rac1 overexpression is associated with redistribution of Rac1 at the plasma membrane only in aggressive tumor. 10 But among the few studies that have monitored Rho GTPase activity in human tumors, the correlation between expression levels of Rho GTPases and their activities is not so obvious. For example, in chronic lymphocytic leukemia, Rac1 activity is increased but no changes in its expression levels have been reported.…”

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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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“…Nevertheless, activation of Rac signaling pathways is believed to contribute to human oncogenesis. Overexpression of: Rac1 in breast tumors, 5 basal cell carcinoma 6 and in hairy cell leukaemia; 7 of an alternatively spliced form Rac1b in colorectal 8 and breast tumors; 9 and of Rac2 in head and neck squamous-cell carcinoma, 10 likely plays a role in the development of these cancers. In addition, examples of alterations to the exchange factors that activate Rac include overexpression of Vav1 in neuroblastoma 11,12 and βPix-a in breast cancer, 13 expression of alternatively spliced forms of ARHGEF5/TIM in breast tumors 14 and mutation and consequent activation of TIAM1 in renal cell carcinomas.…”

Section: Rac Transformationmentioning

confidence: 99%

Rac Transformation: The Actin Connection

Olson¹

2004

Cancer Biology & Therapy

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Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b

Cited by 373 publications

References 32 publications

Specificity and Mechanism of Action of EHT 1864, a Novel Small Molecule Inhibitor of Rac Family Small GTPases

Specificity and Mechanism of Action of EHT 1864, a Novel Small Molecule Inhibitor of Rac Family Small GTPases

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

Rac Transformation: The Actin Connection

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