Rho GTPases: functions and association with cancer

Ellenbroek, Saskia I.J.; Collard, John G.

doi:10.1007/s10585-007-9119-1

Cited by 246 publications

(217 citation statements)

References 157 publications

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“…Because of the lack of evidence regarding Rac1 mutations in human cancers, deregulated Rac1 activity is closely associated with the elevated expression or aberrant activation of Rac1-associated guanine nucleotide exchange factors (GEFs). 27 Thus, FAK may activate Rac1 in OSCC cells by phosphorylating Rac1-associated GEFs. This notion is supported by the observations that Tiam1 and Vav2, two Rac1-associated GEFs, can be phosphorylated by c-Src and, in turn, leads to Rac1 activation and cell invasion.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

Yuan

2016

Laboratory Investigation

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Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. Despite advances in diagnosis and therapy, treatment options for patients with metastatic OSCC are few, due in part to the limited understanding of the molecular events involved in the invasion and metastasis of OSCC. In this study, we investigated the expression of focal adhesion kinase (FAK) and its tyrosine 397 phosphorylation (pY397) in the tissue specimens of OSCC. The roles of pY397 in regulating the activities of Rac1 and cortactin and the invasive properties of OSCC cells were further determined. Results from immunohistochemical analyses in 9 benign, 19 premalignant, and 19 malignant oral tissues showed that the immunoreactivity of FAK was observed in 5 benign (56%), 19 premalignant (100%), and 18 malignant tissues (95%), whereas the immunoreactivity of pY397 was only found in 1 of 9 (11%) benign lesions but was observed in 9 premalignant (47%) and 12 malignant (63%) lesions. Compared with the low-invading SCC4 cells, the high-invading OECM-1 cells exhibited higher levels of FAK expression and pY397, correlating with higher levels of GTP-bound Rac1 and cortactin phosphorylation. Manipulation of FAK expression or Y397 phosphorylation in SCC4, FaDu, OECM-1, or HSC-3 cells regulated their Rac1 activities and invasive properties. Furthermore, treatment of NSC23766, a Rac1-specific inhibitor, in OECM-1 and HSC-3 cells led to reduced invasive properties. Nevertheless, knockdown of FAK expression or suppression of pY397 had no effect on the cortactin activity in OECM-1 cells. The data collectively suggest that pY397 plays critical roles in the FAK-promoted Rac1 activation and invasive properties in OSCC cells. Thus, the inhibition of FAK phosphorylation at Y397 or Rac1 activity can serve as a therapeutic strategy for treating patients with metastatic OSCC. Oral squamous cell carcinoma (OSCC) is the most common malignancy occurring in the oral cavity that usually arises from the buccal mucosa and tongue. During the tumor progression, OSCC cells gradually spread and invade to neighboring tissues, including the nasal cavity or the maxillary facial structures, and eventually metastasize to neck lymph nodes and distant organs. 1 Similar to other malignant diseases, tumor metastasis is a great challenge for the treatment of OSCC. This notion is supported by the fact that only 50% of diagnosed OSCC patients can survive for 5 years, and this is mainly because OSCC patients continue to die from tumor relapse at regional or distant sites. 2 Despite advances in diagnosis and therapy in past decades, the promising strategy for treating patients with metastatic OSCC is still underdeveloped, due in part to the limited understanding of the molecular events involved in invasion and metastasis of OSCC. The underlying molecular basis of OSCC metastasis deserves intensive study.Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase and functionally involves the regulatory processes of multiple cellular events, including adhesion, migration, invasion, prolifer...

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Section: Discussionmentioning

confidence: 99%

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

Yuan

2016

Laboratory Investigation

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“…Mammary acini are hollow samples when compared with the low or undetectable expression detected in normal tissue samples. 6,[12][13][14] In vitro and in vivo studies have shown important roles for Cdc42 in regulating diverse cellular processes such as cell cycle progression and mitosis, polarity, survival, differentiation and stem cell function. Increasing evidence suggests that Cdc42 may play distinct roles in different cell and tissue types, and whether Cdc42 is crucial during normal MEC morphogenesis remains unknown.…”

Section: Introductionmentioning

confidence: 99%

The Rho GTPase Cdc42 is required for primary mammary epithelial cell morphogenesis in vitro

Bray¹,

Brakebusch

Vargo-Gogola

2011

Small GTPases

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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.…”

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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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Rho GTPases: functions and association with cancer

Cited by 246 publications

References 157 publications

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells

The Rho GTPase Cdc42 is required for primary mammary epithelial cell morphogenesis in vitro

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

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