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Open AccessEditorial

Small GTPases in Cancer: Still Signaling the Way

by Paulo Matos

Cancers 2021, 13(7), 1500; https://doi.org/10.3390/cancers13071500 - 25 Mar 2021

Cited by 3 | Viewed by 1775

Abstract

In recent decades, many advances in the early diagnosis and treatment of cancer have been witnessed [...] Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

Research

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36 pages, 4176 KiB

Open AccessArticle

TRPM8-Rap1A Interaction Sites as Critical Determinants for Adhesion and Migration of Prostate and Other Epithelial Cancer Cells

by Giorgia Chinigò, Guillaume P. Grolez, Madelaine Audero, Alexandre Bokhobza, Michela Bernardini, Julien Cicero, Robert-Alain Toillon, Quentin Bailleul, Luca Visentin, Federico Alessandro Ruffinatti, Guillaume Brysbaert, Marc F. Lensink, Jerome De Ruyck, Anna Rita Cantelmo, Alessandra Fiorio Pla and Dimitra Gkika

Cancers 2022, 14(9), 2261; https://doi.org/10.3390/cancers14092261 - 30 Apr 2022

Cited by 10 | Viewed by 3348

Abstract

Emerging evidence indicates that the TRPM8 channel plays an important role in prostate cancer (PCa) progression, by impairing the motility of these cancer cells. Here, we reveal a novel facet of PCa motility control via direct protein-protein interaction (PPI) of the channel with [...] Read more.

Emerging evidence indicates that the TRPM8 channel plays an important role in prostate cancer (PCa) progression, by impairing the motility of these cancer cells. Here, we reveal a novel facet of PCa motility control via direct protein-protein interaction (PPI) of the channel with the small GTPase Rap1A. The functional interaction of the two proteins was assessed by active Rap1 pull-down assays and live-cell imaging experiments. Molecular modeling analysis allowed the identification of four putative residues involved in TRPM8-Rap1A interaction. Point mutations of these sites impaired PPI as shown by GST-pull-down, co-immunoprecipitation, and PLA experiments and revealed their key functional role in the adhesion and migration of PC3 prostate cancer cells. More precisely, TRPM8 inhibits cell migration and adhesion by trapping Rap1A in its GDP-bound inactive form, thus preventing its activation at the plasma membrane. In particular, residues E207 and Y240 in the sequence of TRPM8 and Y32 in that of Rap1A are critical for the interaction between the two proteins not only in PC3 cells but also in cervical (HeLa) and breast (MCF-7) cancer cells. This study deepens our knowledge of the mechanism through which TRPM8 would exert a protective role in cancer progression and provides new insights into the possible use of TRPM8 as a new therapeutic target in cancer treatment. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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22 pages, 3132 KiB

Open AccessArticle

Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells

by Joana F. S. Pereira, Cláudia Bessa, Paulo Matos and Peter Jordan

Cancers 2022, 14(6), 1393; https://doi.org/10.3390/cancers14061393 - 9 Mar 2022

Cited by 7 | Viewed by 2946

Abstract

An inflammatory microenvironment is a tumour-promoting condition that provides survival signals to which cancer cells respond with gene expression changes. One example is the alternative splicing variant Rat Sarcoma Viral Oncogene Homolog (Ras)-Related C3 Botulinum Toxin Substrate 1 (RAC1)B, which we previously identified [...] Read more.

An inflammatory microenvironment is a tumour-promoting condition that provides survival signals to which cancer cells respond with gene expression changes. One example is the alternative splicing variant Rat Sarcoma Viral Oncogene Homolog (Ras)-Related C3 Botulinum Toxin Substrate 1 (RAC1)B, which we previously identified in a subset of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-mutated colorectal tumours. RAC1B was also increased in samples from inflammatory bowel disease patients or in an acute colitis mouse model. Here, we used an epithelial-like layer of polarized Caco-2 or T84 colorectal cancer (CRC) cells in co-culture with fibroblasts, monocytes or macrophages and analysed the effect on RAC1B expression in the CRC cells by RT-PCR, Western blot and confocal fluorescence microscopy. We found that the presence of cancer-associated fibroblasts and M1 macrophages induced the most significant increase in RAC1B levels in the polarized CRC cells, accompanied by a progressive loss of epithelial organization. Under these conditions, we identified interleukin (IL)-6 as the main trigger for the increase in RAC1B levels, associated with Signal Transducer and Activator of Transcription (STAT)3 activation. IL-6 neutralization by a specific antibody abrogated both RAC1B overexpression and STAT3 phosphorylation in polarized CRC cells. Our data identify that pro-inflammatory extracellular signals from stromal cells can trigger the overexpression of tumour-related RAC1B in polarized CRC cells. The results will help to understand the tumour-promoting effect of inflammation and identify novel therapeutic strategies. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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18 pages, 2775 KiB

Open AccessArticle

MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells

by Márcia Faria, Rita Domingues, Maria João Bugalho, Paulo Matos and Ana Luísa Silva

Cancers 2021, 13(22), 5861; https://doi.org/10.3390/cancers13225861 - 22 Nov 2021

Cited by 4 | Viewed by 2281

Abstract

The Sodium/Iodide Symporter (NIS) is responsible for the active transport of iodide into thyroid follicular cells. Differentiated thyroid carcinomas (DTCs) usually preserve the functional expression of NIS, allowing the use of radioactive iodine (RAI) as the treatment of choice for metastatic disease. However, [...] Read more.

The Sodium/Iodide Symporter (NIS) is responsible for the active transport of iodide into thyroid follicular cells. Differentiated thyroid carcinomas (DTCs) usually preserve the functional expression of NIS, allowing the use of radioactive iodine (RAI) as the treatment of choice for metastatic disease. However, a significant proportion of patients with advanced forms of TC become refractory to RAI therapy and no effective therapeutic alternatives are available. Impaired iodide uptake is mainly caused by the defective functional expression of NIS, and this has been associated with several pathways linked to malignant transformation. MAPK signaling has emerged as one of the main pathways implicated in thyroid tumorigenesis, and its overactivation has been associated with the downregulation of NIS expression. Thus, several strategies have been developed to target the MAPK pathway attempting to increase iodide uptake in refractory DTC. However, MAPK inhibitors have had only partial success in restoring NIS expression and, in most cases, it remained insufficient to allow effective treatment with RAI. In a previous work, we have shown that the activity of the small GTPase RAC1 has a positive impact on TSH-induced NIS expression and iodide uptake in thyroid cells. RAC1 is a downstream effector of NRAS, but not of BRAF. Therefore, we hypothesized that the positive regulation induced by RAC1 on NIS could be a relevant signaling cue in the mechanism underlying the differential response to MEK inhibitors, observed between NRAS- and BRAF-mutant tumors. In the present study, we found that the recovery of NIS expression induced through MAPK pathway inhibition can be enhanced by potentiating RAC1 activity in thyroid cell systems. The negative impact on NIS expression induced by the MAPK-activating alterations, NRAS Q61R and BRAF V600E, was partially reversed by the presence of the MEK 1/2 inhibitors AZD6244 and CH5126766. Notably, the inhibition of RAC1 signaling partially blocked the positive impact of MEK inhibition on NIS expression in NRAS Q61R cells. Conversely, the presence of active RAC1 considerably improved the rescue of NIS expression in BRAF V600E thyroid cells treated with MEK inhibitors. Overall, our data support an important role for RAC1 signaling in enhancing MAPK inhibition in the context of RAI therapy in DTC, opening new opportunities for therapeutic intervention. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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28 pages, 5437 KiB

Open AccessArticle

Analysis of NIS Plasma Membrane Interactors Discloses Key Regulation by a SRC/RAC1/PAK1/PIP5K/EZRIN Pathway with Potential Implications for Radioiodine Re-Sensitization Therapy in Thyroid Cancer

by Márcia Faria, Rita Domingues, Maria João Bugalho, Ana Luísa Silva and Paulo Matos

Cancers 2021, 13(21), 5460; https://doi.org/10.3390/cancers13215460 - 30 Oct 2021

Cited by 8 | Viewed by 3144

Abstract

The functional expression of the sodium–iodide symporter (NIS) at the membrane of differentiated thyroid cancer (DTC) cells is the cornerstone for the use of radioiodine (RAI) therapy in these malignancies. However, NIS gene expression is frequently downregulated in malignant thyroid tissue, and 30% [...] Read more.

The functional expression of the sodium–iodide symporter (NIS) at the membrane of differentiated thyroid cancer (DTC) cells is the cornerstone for the use of radioiodine (RAI) therapy in these malignancies. However, NIS gene expression is frequently downregulated in malignant thyroid tissue, and 30% to 50% of metastatic DTCs become refractory to RAI treatment, which dramatically decreases patient survival. Several strategies have been attempted to increase the NIS mRNA levels in refractory DTC cells, so as to re-sensitize refractory tumors to RAI. However, there are many RAI-refractory DTCs in which the NIS mRNA and protein levels are relatively abundant but only reduced levels of iodide uptake are detected, suggesting a posttranslational failure in the delivery of NIS to the plasma membrane (PM), or an impaired residency at the PM. Because little is known about the molecules and pathways regulating NIS delivery to, and residency at, the PM of thyroid cells, we here employed an intact-cell labeling/immunoprecipitation methodology to selectively purify NIS-containing macromolecular complexes from the PM. Using mass spectrometry, we characterized and compared the composition of NIS PM complexes to that of NIS complexes isolated from whole cell (WC) lysates. Applying gene ontology analysis to the obtained MS data, we found that while both the PM-NIS and WC-NIS datasets had in common a considerable number of proteins involved in vesicle transport and protein trafficking, the NIS PM complexes were particularly enriched in proteins associated with the regulation of the actin cytoskeleton. Through a systematic validation of the detected interactions by co-immunoprecipitation and Western blot, followed by the biochemical and functional characterization of the contribution of each interactor to NIS PM residency and iodide uptake, we were able to identify a pathway by which the PM localization and function of NIS depends on its binding to SRC kinase, which leads to the recruitment and activation of the small GTPase RAC1. RAC1 signals through PAK1 and PIP5K to promote ARP2/3-mediated actin polymerization, and the recruitment and binding of the actin anchoring protein EZRIN to NIS, promoting its residency and function at the PM of normal and TC cells. Besides providing novel insights into the regulation of NIS localization and function at the PM of TC cells, our results open new venues for therapeutic intervention in TC, namely the possibility of modulating abnormal SRC signaling in refractory TC from a proliferative/invasive effect to the re-sensitization of these tumors to RAI therapy by inducing NIS retention at the PM. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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22 pages, 5918 KiB

Open AccessArticle

RAB7A Regulates Vimentin Phosphorylation through AKT and PAK

by Roberta Romano, Matteo Calcagnile, Azzurra Margiotta, Lorenzo Franci, Mario Chiariello, Pietro Alifano and Cecilia Bucci

Cancers 2021, 13(9), 2220; https://doi.org/10.3390/cancers13092220 - 6 May 2021

Cited by 13 | Viewed by 3025

Abstract

RAB7A is a small GTPase that controls the late endocytic pathway but also cell migration through RAC1 (Ras-related C3 botulinum toxin substrate 1) and vimentin. In fact, RAB7A regulates vimentin phosphorylation at different sites and vimentin assembly, and, in this study, we identified [...] Read more.

RAB7A is a small GTPase that controls the late endocytic pathway but also cell migration through RAC1 (Ras-related C3 botulinum toxin substrate 1) and vimentin. In fact, RAB7A regulates vimentin phosphorylation at different sites and vimentin assembly, and, in this study, we identified vimentin domains interacting with RAB7A. As several kinases could be responsible for vimentin phosphorylation, we investigated whether modulation of RAB7A expression affects the activity of these kinases. We discovered that RAB7A regulates AKT and PAK1, and we demonstrated that increased vimentin phosphorylation at Ser38 (Serine 38), observed upon RAB7A overexpression, is due to AKT activity. As AKT and PAK1 are key regulators of several cellular events, we investigated if RAB7A could have a role in these processes by modulating AKT and PAK1 activity. We found that RAB7A protein levels affected beta-catenin and caspase 9 expression. We also observed the downregulation of cofilin-1 and decreased matrix metalloproteinase 2 (MMP2) activity upon RAB7A silencing. Altogether these results demonstrate that RAB7A regulates AKT and PAK1 kinases, affecting their downstream effectors and the processes they regulate, suggesting that RAB7A could have a role in a number of cancer hallmarks. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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Review

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17 pages, 1659 KiB

Open AccessReview

RANBP1 (RAN Binding Protein 1): The Missing Genetic Piece in Cancer Pathophysiology and Other Complex Diseases

by Salvatore Audia, Carolina Brescia, Vincenzo Dattilo, Lucia D’Antona, Pierluigi Calvano, Rodolfo Iuliano, Francesco Trapasso, Nicola Perrotti and Rosario Amato

Cancers 2023, 15(2), 486; https://doi.org/10.3390/cancers15020486 - 12 Jan 2023

Cited by 9 | Viewed by 3780

Abstract

RANBP1 encoded by RANBP1 or HTF9A (Hpall Tiny Fragments Locus 9A), plays regulatory functions of the RAN-network, belonging to the RAS superfamily of small GTPases. Through this function, RANBP1 regulates the RANGAP1 activity and, thus, the fluctuations between GTP-RAN and GDP-RAN. In the [...] Read more.

RANBP1 encoded by RANBP1 or HTF9A (Hpall Tiny Fragments Locus 9A), plays regulatory functions of the RAN-network, belonging to the RAS superfamily of small GTPases. Through this function, RANBP1 regulates the RANGAP1 activity and, thus, the fluctuations between GTP-RAN and GDP-RAN. In the light of this, RANBP1 take actions in maintaining the nucleus–cytoplasmic gradient, thus making nuclear import–export functional. RANBP1 has been implicated in the inter-nuclear transport of proteins, nucleic acids and microRNAs, fully contributing to cellular epigenomic signature. Recently, a RANBP1 diriment role in spindle checkpoint formation and nucleation has emerged, thus constituting an essential element in the control of mitotic stability. Over time, RANBP1 has been demonstrated to be variously involved in human cancers both for the role in controlling nuclear transport and RAN activity and for its ability to determine the efficiency of the mitotic process. RANBP1 also appears to be implicated in chemo-hormone and radio-resistance. A key role of this small-GTPases related protein has also been demonstrated in alterations of axonal flow and neuronal plasticity, as well as in viral and bacterial metabolism and in embryological maturation. In conclusion, RANBP1 appears not only to be an interesting factor in several pathological conditions but also a putative target of clinical interest. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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15 pages, 3867 KiB

Open AccessReview

The Role of Fast-Cycling Atypical RHO GTPases in Cancer

by Pontus Aspenström

Cancers 2022, 14(8), 1961; https://doi.org/10.3390/cancers14081961 - 13 Apr 2022

Cited by 10 | Viewed by 2579

Abstract

The RHO GTPases comprise a subfamily within the RAS superfamily of small GTP-hydrolyzing enzymes and have primarily been ascribed roles in regulation of cytoskeletal dynamics in eukaryotic cells. An oncogenic role for the RHO GTPases has been disregarded, as no activating point mutations [...] Read more.

The RHO GTPases comprise a subfamily within the RAS superfamily of small GTP-hydrolyzing enzymes and have primarily been ascribed roles in regulation of cytoskeletal dynamics in eukaryotic cells. An oncogenic role for the RHO GTPases has been disregarded, as no activating point mutations were found for genes encoding RHO GTPases. Instead, dysregulated expression of RHO GTPases and their regulators have been identified in cancer, often in the context of increased tumor cell migration and invasion. In the new landscape of cancer genomics, activating point mutations in members of the RHO GTPases have been identified, in particular in RAC1, RHOA, and CDC42, which has suggested that RHO GTPases can indeed serve as oncogenes in certain cancer types. This review describes the current knowledge of these cancer-associated mutant RHO GTPases, with a focus on how their altered kinetics can contribute to cancer progression. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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24 pages, 1124 KiB

Open AccessReview

Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities

by Sapana Bansod, Paarth B. Dodhiawala and Kian-Huat Lim

Cancers 2021, 13(21), 5481; https://doi.org/10.3390/cancers13215481 - 31 Oct 2021

Cited by 12 | Viewed by 4375

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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28 pages, 1087 KiB

Open AccessFeature PaperReview

RHO GTPase-Related Long Noncoding RNAs in Human Cancers

by Mahsa Saliani, Amin Mirzaiebadizi, Niloufar Mosaddeghzadeh and Mohammad Reza Ahmadian

Cancers 2021, 13(21), 5386; https://doi.org/10.3390/cancers13215386 - 27 Oct 2021

Cited by 10 | Viewed by 3168

Abstract

RHO GTPases are critical signal transducers that regulate cell adhesion, polarity, and migration through multiple signaling pathways. While all these cellular processes are crucial for the maintenance of normal cell homeostasis, disturbances in RHO GTPase-associated signaling pathways contribute to different human diseases, including [...] Read more.

RHO GTPases are critical signal transducers that regulate cell adhesion, polarity, and migration through multiple signaling pathways. While all these cellular processes are crucial for the maintenance of normal cell homeostasis, disturbances in RHO GTPase-associated signaling pathways contribute to different human diseases, including many malignancies. Several members of the RHO GTPase family are frequently upregulated in human tumors. Abnormal gene regulation confirms the pivotal role of lncRNAs as critical gene regulators, and thus, they could potentially act as oncogenes or tumor suppressors. lncRNAs most likely act as sponges for miRNAs, which are known to be dysregulated in various cancers. In this regard, the significant role of miRNAs targeting RHO GTPases supports the view that the aberrant expression of lncRNAs may reciprocally change the intensity of RHO GTPase-associated signaling pathways. In this review article, we summarize recent advances in lncRNA research, with a specific focus on their sponge effects on RHO GTPase-targeting miRNAs to crucially mediate gene expression in different cancer cell types and tissues. We will focus in particular on five members of the RHO GTPase family, including RHOA, RHOB, RHOC, RAC1, and CDC42, to illustrate the role of lncRNAs in cancer progression. A deeper understanding of the widespread dysregulation of lncRNAs is of fundamental importance for confirmation of their contribution to RHO GTPase-dependent carcinogenesis. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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18 pages, 2417 KiB

Open AccessReview

Skin Cancers and the Contribution of Rho GTPase Signaling Networks to Their Progression

by Alessandra Pecora, Justine Laprise, Manel Dahmene and Mélanie Laurin

Cancers 2021, 13(17), 4362; https://doi.org/10.3390/cancers13174362 - 28 Aug 2021

Cited by 4 | Viewed by 3405

Abstract

Skin cancers are the most common cancers worldwide. Among them, melanoma, basal cell carcinoma of the skin and cutaneous squamous cell carcinoma are the three major subtypes. These cancers are characterized by different genetic perturbations even though they are similarly caused by a [...] Read more.

Skin cancers are the most common cancers worldwide. Among them, melanoma, basal cell carcinoma of the skin and cutaneous squamous cell carcinoma are the three major subtypes. These cancers are characterized by different genetic perturbations even though they are similarly caused by a lifelong exposure to the sun. The main oncogenic drivers of skin cancer initiation have been known for a while, yet it remains unclear what are the molecular events that mediate their oncogenic functions and that contribute to their progression. Moreover, patients with aggressive skin cancers have been known to develop resistance to currently available treatment, which is urging us to identify new therapeutic opportunities based on a better understanding of skin cancer biology. More recently, the contribution of cytoskeletal dynamics and Rho GTPase signaling networks to the progression of skin cancers has been highlighted by several studies. In this review, we underline the various perturbations in the activity and regulation of Rho GTPase network components that contribute to skin cancer development, and we explore the emerging therapeutic opportunities that are surfacing from these studies. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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25 pages, 2709 KiB

Open AccessReview

Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance

by Anxo Rio-Vilariño, Laura del Puerto-Nevado, Jesús García-Foncillas and Arancha Cebrián

Cancers 2021, 13(15), 3757; https://doi.org/10.3390/cancers13153757 - 26 Jul 2021

Cited by 4 | Viewed by 3131

Abstract

Colorectal cancer remains among the cancers with the highest incidence, prevalence, and mortality worldwide. Although the development of targeted therapies against the EGFR and VEGFR membrane receptors has considerably improved survival in these patients, the appearance of resistance means that their success is [...] Read more.

Colorectal cancer remains among the cancers with the highest incidence, prevalence, and mortality worldwide. Although the development of targeted therapies against the EGFR and VEGFR membrane receptors has considerably improved survival in these patients, the appearance of resistance means that their success is still limited. Overactivation of several members of the Ras-GTPase family is one of the main actors in both tumour progression and the lack of response to cytotoxic and targeted therapies. This fact has led many resources to be devoted over the last decades to the development of targeted therapies against these proteins. However, they have not been as successful as expected in their move to the clinic so far. In this review, we will analyse the role of these Ras-GTPases in the emergence and development of colorectal cancer and their relationship with resistance to targeted therapies, as well as the status and new advances in the design of targeted therapies against these proteins and their possible clinical implications. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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21 pages, 1447 KiB

Open AccessReview

The Small GTPase RAC1B: A Potent Negative Regulator of-and Useful Tool to Study-TGFβ Signaling

by Hendrik Ungefroren, Ulrich F. Wellner, Tobias Keck, Hendrik Lehnert and Jens-Uwe Marquardt

Cancers 2020, 12(11), 3475; https://doi.org/10.3390/cancers12113475 - 22 Nov 2020

Cited by 9 | Viewed by 2816

Abstract

RAC1 and its alternatively spliced isoform, RAC1B, are members of the Rho family of GTPases. Both isoforms are involved in the regulation of actin cytoskeleton remodeling, cell motility, cell proliferation, and epithelial–mesenchymal transition (EMT). Compared to RAC1, RAC1B exhibits a number of distinctive [...] Read more.

RAC1 and its alternatively spliced isoform, RAC1B, are members of the Rho family of GTPases. Both isoforms are involved in the regulation of actin cytoskeleton remodeling, cell motility, cell proliferation, and epithelial–mesenchymal transition (EMT). Compared to RAC1, RAC1B exhibits a number of distinctive features with respect to tissue distribution, downstream signaling and a role in disease conditions like inflammation and cancer. The subcellular locations and interaction partners of RAC1 and RAC1B vary depending on their activation state, which makes RAC1 and RAC1B ideal candidates to establish cross-talk with cancer-associated signaling pathways—for instance, interactions with signaling by transforming growth factor β (TGFβ), a known tumor promoter. Although RAC1 has been found to promote TGFβ-driven tumor progression, recent observations in pancreatic carcinoma cells surprisingly revealed that RAC1B confers anti-oncogenic properties, i.e., through inhibiting TGFβ-induced EMT. Since then, an unexpected array of mechanisms through which RAC1B cross-talks with TGFβ signaling has been demonstrated. However, rather than being uniformly inhibitory, RAC1B interacts with TGFβ signaling in a way that results in the selective blockade of tumor-promoting pathways, while concomitantly allowing tumor-suppressive pathways to proceed. In this review article, we are going to discuss the specific interactions between RAC1B and TGFβ signaling, which occur at multiple levels and include various components such as ligands, receptors, cytosolic mediators, transcription factors, and extracellular inhibitors of TGFβ ligands. Full article

(This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis)

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