Oncogenic mutations on Rac1 affect global intrinsic dynamics underlying GTP and PAK1 binding

Acuner-Ozbabacan, Saliha Ece; Sumbul, Fidan; Torun, Hamdi; Haliloğlu, Türkan

doi:10.1016/j.bpj.2021.01.016

Cited by 15 publications

(11 citation statements)

References 58 publications

(52 reference statements)

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“…10 Å) from the nucleotide. In a recent study on the Rac1-PAK1 complex, where the binding is investigated with the Gaussian Network Model (GNM) and molecular dynamics, Rac1 P29S also exhibits a higher flexibility in the Switch I region in both GTP-binding and PAK1-binding residues …”

Section: Discussionmentioning

confidence: 99%

Mechanistic Differences of Activation of Rac1^P29S and Rac1^A159V

et al. 2021

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Rac1 is a small GTPase that plays key roles in actin reorganization, cell motility, and cell survival/growth as well as in various cancer types and neurodegenerative diseases. Similar to other Ras superfamily GTPases, Rac1 switches between active GTP-bound and inactive GDP-bound states. Switch I and II regions open and close during GDP/GTP exchange. P29S and A159V (paralogous to K-Ras A146 ) mutations are the two most common somatic mutations of Rac1. Rac1 P29S is a known hotspot for melanoma, whereas Rac1 A159V most commonly occurs in head and neck cancer. To investigate how these substitutions induce the Rac1 dynamics, we used atomistic molecular dynamics simulations on the wild-type Rac1 and two mutant systems (P29S and A159V) in the GTP bound state, and on the wild-type Rac1 and P29S mutated system in the GDP bound state. Here, we show that P29S and A159V mutations activate Rac1 with different mechanisms. In Rac1 P29S -GTP, the substitution increases the flexibility of Switch I based on RMSF and dihedral angle calculations and leads to an open conformation. We propose that the open Switch I conformation is one of the underlying reasons for rapid GDP/GTP exchange of Rac1 P29S . On the other hand, in Rac1 A159V -GTP, some of the contacts of the guanosine ring of GTP with Rac1 are temporarily lost, enabling the guanosine ring to move toward Switch I and subsequently close the switch. Rac1 A159V -GTP adopts a Ras state 2 like conformation, where both switch regions are in closed conformation and Thr35 forms a hydrogen bond with the nucleotide.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Differences of Activation of Rac1^P29S and Rac1^A159V

et al. 2021

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“…Conversely, Rac1 is often overexpressed and hyperactivated in cancers, notably in breast, colon, skin (melanoma), liver and lung cancers [ 31 , 41 , 42 , 43 ]. Moreover, Rac1 gain-of-function mutations have been identified in recent years, such as the two somatic mutations Rac1 P29S and Rac1 A159V , respectively detected in melanoma and in head-and-neck cancers [ 44 , 45 , 46 ], and occasionally observed in colon, thyroid, and lung cancers [ 47 ]. These variants represent fast cycling mutants that contribute to expand tumor phenotypes and confer resistance to targeted therapies.…”

Section: Rac1 Structure and Functionmentioning

confidence: 99%

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

Sauzeau

Beignet²,

Bailly

2022

Biomedicines

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Bladder pathologies, very common in the aged population, have a considerable negative impact on quality of life. Novel targets are needed to design drugs and combinations to treat diseases such as overactive bladder and bladder cancers. A promising new target is the ubiquitous Rho GTPase Rac1, frequently dysregulated and overexpressed in bladder pathologies. We have analyzed the roles of Rac1 in different bladder pathologies, including bacterial infections, diabetes-induced bladder dysfunctions and bladder cancers. The contribution of the Rac1 protein to tumorigenesis, tumor progression, epithelial-mesenchymal transition of bladder cancer cells and their metastasis has been analyzed. Small molecules selectively targeting Rac1 have been discovered or designed, and two of them—NSC23766 and EHT 1864—have revealed activities against bladder cancer. Their mode of interaction with Rac1, at the GTP binding site or the guanine nucleotide exchange factors (GEF) interaction site, is discussed. Our analysis underlines the possibility of targeting Rac1 with small molecules with the objective to combat bladder dysfunctions and to reduce lower urinary tract symptoms. Finally, the interest of a Rac1 inhibitor to treat advanced chemoresistance prostate cancer, while reducing the risk of associated bladder dysfunction, is discussed. There is hope for a better management of bladder pathologies via Rac1-targeted approaches.

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“…The most mature mechanism of Rac1 mediated cytoskeletal recombination is through PAKs (P21 activated kinase) (32). Both cell proliferation and cell movement require actin recombination, which is controlled by Rac1 and PAK1 (31).…”

Section: Rac1 Regulates Cell Adhesion Morphology and Movementmentioning

confidence: 99%

Rac1, A Potential Target for Tumor Therapy

et al. 2021

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RAS-related C3 botulinum toxin substrate 1 (Rac.1) is one of the important members of Rho GTPases. It is well known that Rac1 is a cytoskeleton regulation protein that regulates cell adhesion, morphology, and movement. Rac1 is highly expressed in different types of tumors, which is related to poor prognosis. Studies have shown that Rac1 not only participates in the tumor cell cycle, apoptosis, proliferation, invasion, migration and angiogenesis, but also participates in the regulation of tumor stem cell, thus promoting the occurrence of tumors. Rac1 also plays a key role in anti-tumor therapy and participates in immune escape mediated by the tumor microenvironment. In addition, the good prospects of Rac1 inhibitors in cancer prevention and treatment are exciting. Therefore, Rac1 is considered as a potential target for the prevention and treatment of cancer. The necessity and importance of Rac1 are obvious, but it still needs further study.

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Oncogenic mutations on Rac1 affect global intrinsic dynamics underlying GTP and PAK1 binding

Cited by 15 publications

References 58 publications

Mechanistic Differences of Activation of Rac1^P29S and Rac1^A159V

Mechanistic Differences of Activation of Rac1^P29S and Rac1^A159V

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

Rac1, A Potential Target for Tumor Therapy

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Oncogenic mutations on Rac1 affect global intrinsic dynamics underlying GTP and PAK1 binding

Cited by 15 publications

References 58 publications

Mechanistic Differences of Activation of Rac1P29S and Rac1A159V

Mechanistic Differences of Activation of Rac1P29S and Rac1A159V

Rac1 as a Target to Treat Dysfunctions and Cancer of the Bladder

Rac1, A Potential Target for Tumor Therapy

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Product

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Mechanistic Differences of Activation of Rac1^P29S and Rac1^A159V

Mechanistic Differences of Activation of Rac1^P29S and Rac1^A159V