Proteomic analysis of Rac1 signaling regulation by guanine nucleotide exchange factors

Marei, Hadir; Carpy, Alejandro; Maček, Boris; Malliri, Angeliki

doi:10.1080/15384101.2016.1183852

Cited by 20 publications

(15 citation statements)

References 60 publications

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“…D and E), it would be interesting to explore the role of ARHGEF7 changes in these phenomena. Also noteworthy is that the identity of the activating GEF determines the pattern of protein‐protein interactions and, hence, the exact consequences of RAC1 activation . Therefore, it is worthwhile exploring whether only a subset of GEFs can confer RAC1‐mediated protection from vemurafenib.…”

Section: Discussionmentioning

confidence: 99%

P21‐activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells

Babagana

Johnson

Slabodkin

et al. 2017

Molecular Carcinogenesis

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BRAF is a commonly mutated oncogene in various human malignancies and a target of a new class of anti-cancer agents, BRAF-inhibitors (BRAFi). The initial enthusiasm for these agents, based on the early successes in the management of metastatic melanoma, is now challenged by the mounting evidence of intrinsic BRAFi-insensitivity in many BRAF-mutated tumors, by the scarcity of complete responses, and by the inevitable emergence of drug resistance in initially responsive cases. These setbacks put an emphasis on discovering the means to increase the efficacy of BRAFi and to prevent or overcome BRAFi-resistance. We explored the role of p21-activated kinases (PAKs), in particular PAK1, in BRAFi response. BRAFi lowered the levels of active PAK1 in treated cells. An activated form of PAK1 conferred BRAFi-resistance on otherwise sensitive cells, while genetic or pharmacologic suppression of PAK1 had a sensitizing effect. While activation of AKT1 and RAC1 proto-oncogenes increased BRAFi-tolerance, the protective effect was negated in the presence of PAK inhibitors. Furthermore, combining otherwise ineffective doses of PAK- and BRAF-inhibitors synergistically affected intrinsically BRAFi-resistant cells. Considering the high incidence of PAK1 activation in cancers, our findings suggests PAK inhibition as a strategy to augment BRAFi therapy and overcome some of the well-known resistance mechanisms.

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Section: Discussionmentioning

confidence: 99%

P21‐activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells

Babagana

Johnson

Slabodkin

et al. 2017

Molecular Carcinogenesis

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“… 16 Functional validation of Tiam1-enriched Rac1 interactors identified from our proteomic screen indicated that Tiam1-mediated activation of Rac1 enhances Rac1-IQGAP1 binding. 17 Intriguingly, IQGAP1 was shown to disrupt cell-cell contacts via binding to β-catenin and destabilizing the α-catenin-β-catenin-E-cadherin complex. 47 However, increased binding of active Rac1 to IQGAP1 inhibits its binding to β-catenin, thereby stabilizing E-cadherin-mediated cell-cell contacts.…”

Section: Gefs As Master Regulators Of Rac1 Signalingmentioning

confidence: 99%

GEFs: Dual regulation of Rac1 signaling

Marei

Malliri

2016

Small GTPases

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GEFs play a critical role in regulating Rac1 signaling. They serve as signaling nodes converting upstream signals into downstream Rac1-driven cellular responses. Through associating with membrane-bound Rac1, GEFs facilitate the exchange of GDP for GTP, thereby activating Rac1. As a result, Rac1 undergoes conformational changes that mediate its interaction with downstream effectors, linking Rac1 to a multitude of physiological and pathological processes. Interestingly, there are at least 20 GEFs involved in Rac1 activation, suggesting a more complex role of GEFs in regulating Rac1 signaling apart from promoting the exchange of GDP for GTP. Indeed, accumulating evidence implicates GEFs in directing the specificity of Rac1-driven signaling cascades, although the underlying mechanisms were poorly defined. Recently, through conducting a comparative study, we highlighted the role of 2 Rac-specific GEFs, Tiam1 and P-Rex1, in dictating the biological outcome downstream of Rac1. Importantly, further proteomic analysis uncovered a GEF activity-independent function for both GEFs in modulating the Rac1 interactome, which results in the stimulation of GEF-specific signaling cascades. Here, we provide an overview of our recent findings and discuss the role of GEFs as master regulators of Rac1 signaling with a particular focus on GEF-mediated modulation of cell migration following Rac1 activation.

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“… 44 Indeed, comparative quantitative proteomic analysis of the Rac1 interactome revealed that Tiam1 and P-Rex1 stimulate Rac1 association with GEF-specific effector pools that could account for the contrasting roles of these 2 GEFs in regulating Rac1-driven cell migration. 45,46 Thus, all together this highlights the importance of the GEF scaffolding function in mediating specific Rac1-driven signaling cascades in response to different upstream cues.…”

Section: Targeting Rac1 Signaling Regulatory Mechanisms Provides Multmentioning

confidence: 87%

Rac1 in human diseases: The therapeutic potential of targeting Rac1 signaling regulatory mechanisms

2016

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Abnormal Rac1 signaling is linked to a number of debilitating human diseases, including cancer, cardiovascular diseases and neurodegenerative disorders. As such, Rac1 represents an attractive therapeutic target, yet the search for effective Rac1 inhibitors is still underway. Given the adverse effects associated with Rac1 signaling perturbation, cells have evolved several mechanisms to ensure the tight regulation of Rac1 signaling. Thus, characterizing these mechanisms can provide invaluable information regarding major cellular events that lead to aberrant Rac1 signaling. Importantly, this information can be utilized to further facilitate the development of effective pharmacological modulators that can restore normal Rac1 signaling. In this review, we focus on the pathological role of Rac1 signaling, highlighting the benefits and potential drawbacks of targeting Rac1 in a clinical setting. Additionally, we provide an overview of available compounds that target key Rac1 regulatory mechanisms and discuss future therapeutic avenues arising from our understanding of these mechanisms.

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Proteomic analysis of Rac1 signaling regulation by guanine nucleotide exchange factors

Cited by 20 publications

References 60 publications

P21‐activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells

P21‐activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells

GEFs: Dual regulation of Rac1 signaling

Rac1 in human diseases: The therapeutic potential of targeting Rac1 signaling regulatory mechanisms

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