Structural fingerprints, interactions, and signaling networks of RAS family proteins beyond RAS isoforms

Nakhaei‐Rad, Saeideh; Haghighi, Fereshteh; Nouri, Parivash; Adariani, Soheila Rezaei; Lissy, Jana; Jasemi, Neda S. Kazemein; Dvorský, Radovan; Ahmadian, Mohammad Réza

doi:10.1080/10409238.2018.1431605

Cited by 33 publications

(27 citation statements)

References 374 publications

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“…Together with luminal extrusion of effete cells, this enables the constant regeneration of the epithelial lining, the integrity of which is maintained by adhesion junctions between the IECs. It is intriguing to envisage the high level of coordination needed to enable intestinal cells to undergo a series of cell fates during their lifetimepart of which is achieved by members of the superfamily of small GTPases [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context

et al. 2020

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Cancer is the second leading cause of death globally, and colorectal cancer (CRC) is among the five most common cancers. The small GTPase KRAS is an oncogene that is mutated in~30% of all CRCs. Pharmacological treatments of CRC are currently unsatisfactory, but much hope rests on network-centric approaches to drug development and cancer treatment. These approaches, however, require a better understanding of how networks downstream of Ras oncoproteins are connected in a particular tissue contexthere colon and CRC. Previously we have shown that competition for binding to a 'hub' protein, such as Ras, can induce a rewiring of signal transduction networks. In this study, we analysed 56 established and predicted effectors that contain a structural domain with the potential ability to bind to Ras oncoproteins and their link to pathways coordinating intestinal homoeostasis and barrier function. Using protein concentrations in colon tissue and Ras-effector binding affinities, a computational network model was generated that predicted how effectors differentially and competitively bind to Ras in colon context. The model also predicted both qualitative and quantitative changes in Ras-effector complex formations with increased levels of active Rasto simulate its upregulation in cancersimply as an emergent property of competition for the same binding interface on the surface of Ras. We also considered how the number of Ras-effector complexes at the membrane can be increased by additional domains present in some effectors that are recruited to the membrane in response to specific conditions (inputs/stimuli/growth factors) in colon context and CRC.

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Section: Introductionmentioning

confidence: 99%

Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context

et al. 2020

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“…Because of the unsuccessful EGFR targeted therapy for KRAS onc -dependent cancers and the difficulty associated with targeting KRAS onc directly, a great deal of effort has been applied to target downstream effector pathways. The specific interaction of RAS family proteins with downstream effectors regulates various cellular functions 3,77,96,97 . Constitutive activation of downstream effector pathways by oncogenic KRAS results in the uncontrolled growth, proliferation, and survival of cancer cells 98 .…”

Section: Rna Interferencementioning

confidence: 99%

“…With the discovery of the mutational activation of RAS genes in human cancers dating back to the 1960s, extensive studies have been conducted to understand the localization, regulation and signaling of RAS proteins with the ultimate goal of developing anti-RAS drugs for cancer treatment 3 . Somatic mutations, most frequently identified KRAS4B (oncogenic KRAS or KRAS onc ) (COSMIC), contribute to robust gain-of-function effects and to various types of cancers as well as leukemia and lymphoma tumors 19-22 .…”

Section: Introductionmentioning

confidence: 99%

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From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

2019

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Among the numerous oncogenes involved in human cancers, KRAS represents the most studied and best characterized cancer-related genes. Several therapeutic strategies targeting oncogenic KRAS (KRASonc) signaling pathways have been suggested, including the inhibition of synthetic lethal interactions, direct inhibition of KRASonc itself, blockade of downstream KRASonc effectors, prevention of post-translational KRASonc modifications, inhibition of the induced stem cell-like program, targeting of metabolic peculiarities, stimulation of the immune system, inhibition of inflammation, blockade of upstream signaling pathways, targeted RNA replacement, and oncogene-induced senescence. Despite intensive and continuous efforts, KRASonc remains an elusive target for cancer therapy. To highlight the progress to date, this review covers a collection of studies on therapeutic strategies for KRAS published from 1995 to date. An overview of the path of progress from earlier to more recent insights highlight novel opportunities for clinical development towards KRASonc-signaling targeted therapeutics.

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“…R‐Ras is a small GTPase of the Ras family of oncogenes . Despite the close structural similarity to known oncogenes of the Ras family, the function of R‐Ras is distinct from other Ras proteins .…”

Section: Introductionmentioning

confidence: 99%

R‐Ras regulates vascular permeability, but not overall healing in skin wounds

Ketomäki

Vähätupa

May

et al. 2018

Experimental Dermatology

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Wounds close by keratinocytes migrating from the edge of the wound and re‐epithelializing the epidermis. It has been proposed that the major stimuli for wound closure are blood‐derived growth factors, chemokines and cytokines. The small GTPase R‐Ras, a known integrin activator, also regulates vascular permeability during angiogenesis, and blood vessels lacking R‐Ras leak plasma proteins constantly. We explored whether the access to blood‐derived proteins influences skin wound healing in R‐Ras knockout (KO) mice. In skin wounds, R‐Ras expression was mostly restricted to the vasculature in the granulation tissue. Angiogenic blood vessels in the R‐Ras KO mice were significantly more permeable than in wild‐type (WT) controls. Although the distances between epidermal tongues, and the panniculus carnosus muscles, were significantly longer in R‐Ras KO than WT controls before the granulation tissue formation took place, there were no differences in the wound closure or re‐epithelialization rates or granulation tissue formation. These findings were also corroborated in a special splint excision wound model. Our study shows that although R‐Ras does not influence the skin wound healing itself, the blood vessels lacking R‐Ras are leaky and thus could facilitate the access of blood‐derived proteins to the wound.

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Structural fingerprints, interactions, and signaling networks of RAS family proteins beyond RAS isoforms

Cited by 33 publications

References 374 publications

Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context

Analysis of Ras-effector interaction competition in large intestine and colorectal cancer context

From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

R‐Ras regulates vascular permeability, but not overall healing in skin wounds

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