Network Analysis of Oncogenic Ras Activation in Cancer

Stites, Edward C.; Trampont, Paul C.; Ma, Zhiyuan; Ravichandran, Kodi S.

doi:10.1126/science.1144642

Cited by 113 publications

(158 citation statements)

References 19 publications

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“…CNK1 was shown to be required for Src-dependent activation of ERK by vascular endothelial growth factor, but not for basic fibroblast growth factor-or epidermal growth factor-induced, Ras-dependent ERK activation (10,11). This fact may explain why CNK1 knockdown does not impair ERK activation in MDA-MB-231 cells that exhibit a constitutively active Ras (49).…”

Section: Discussionmentioning

confidence: 71%

CNK1 Promotes Invasion of Cancer Cells through NF-κB–Dependent Signaling

Fritz

Radziwill

2010

Molecular Cancer Research

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Hallmarks of cancer cells are uncontrolled proliferation, evasion of apoptosis, angiogenesis, cell invasion, and metastasis, which are driven by oncogenic activation of signaling pathways. Herein, we identify the scaffold protein CNK1 as a mediator of oncogenic signaling that promotes invasion in human breast cancer and cervical cancer cells. Downregulation of CNK1 diminishes the invasiveness of cancer cells and correlates with reduced expression of matrix metalloproteinase 9 (MMP-9) and membrane-type 1 MMP (MT1-MMP). Ectopic expression of CNK1 elevates MT1-MMP promoter activity in a NF-κB-dependent manner. Moreover, CNK1 cooperates with the NF-κB pathway, but not with the extracellular signal-regulated protein kinase pathway, to promote cell invasion. Mechanistically, CNK1 regulates the alternative branch of the NF-κB pathway because knockdown of CNK1 interferes with processing of NF-κB2 p100 to p52 and its localization to the nucleus. In agreement with this, the invasion of CNK1-depleted cells is less sensitive to RelB downregulation compared with the invasion of control cells. Moreover, CNK1-dependent MT1-MMP promoter activation is blocked by RelB siRNA. Thus, CNK1 is an essential mediator of an oncogenic pathway involved in invasion of breast and cervical cancer cells and is therefore a putative target for cancer therapy. Mol Cancer Res; 8(3); 395-406. ©2010 AACR.

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Section: Discussionmentioning

confidence: 71%

CNK1 Promotes Invasion of Cancer Cells through NF-κB–Dependent Signaling

Fritz

Radziwill

2010

Molecular Cancer Research

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“…We assumed that the positive feedback loop could reach saturation, due in part to the limited amount of ROP1 available for its activation. The cellular concentrations of Rho-family proteins (e.g., Rho, Rac, Cdc42) have an estimated range of 2.4-7.5 M (21,22). Given the conserved functions of Rho proteins (including ROPs), we reasoned that the concentration of ROPs in pollen tubes would fall within this range.…”

Section: Resultsmentioning

confidence: 99%

Calcium participates in feedback regulation of the oscillating ROP1 Rho GTPase in pollen tubes

Yang

2009

Proc. Natl. Acad. Sci. U.S.A.

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Biological oscillation occurs at various levels, from cellular signaling to organismal behaviors. Mathematical modeling has allowed a quantitative understanding of slow oscillators requiring changes in gene expression (e.g., circadian rhythms), but few theoretical studies have focused on the rapid oscillation of cellular signaling. The tobacco pollen tube, which exhibits growth bursts every 80 s or so, is an excellent system for investigating signaling oscillation. Pollen tube growth is controlled by a tip-localized ROP1 GTPase, whose activity oscillates in a phase about 90 degrees ahead of growth. We constructed a mathematical model of ROP1 activity oscillation consisting of interlinking positive and negative feedback loops involving F-actin and calcium, ROP1-signaling targets that oscillate in a phase about 20 degrees and 110 degrees behind ROP1 activity, respectively. The model simulates the observed changes in ROP1 activity caused by F-actin disruption and predicts a role for calcium in the negative feedback regulation of the ROP1 activity. Our experimental data strongly support this role of calcium in tip growth. Thus, our findings provide insight into the mechanism of pollen tube growth and the oscillation of cellular signaling.model ͉ ROP1 GTPase ͉ tip growth

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“…Stites et al (14) proposed a protein-level, perturbation-based analysis of unregulated Ras activation associated with cancer and successfully explained the correlation between Ras mutation properties and the known pathological mechanisms of Ras signaling activation. In our opinion, the selection of different dynamic features should not be considered as an inconsistency; the specific biological function to be embodied should be taken into account.…”

Section: Discussionmentioning

confidence: 99%

“…A more quantitative approach is network modeling using ordinary differential equations (ODEs) and mathematical simulations. This well-established method has been successfully used to understand cellular dynamic functionalities and network regulatory principles, including the relationship between genetic mutations and oncogenesis (11)(12)(13)(14)(15). For example, Stites et al (14) studied common oncogenic Ras mutations that affect Ras activation.…”

mentioning

confidence: 99%

“…This well-established method has been successfully used to understand cellular dynamic functionalities and network regulatory principles, including the relationship between genetic mutations and oncogenesis (11)(12)(13)(14)(15). For example, Stites et al (14) studied common oncogenic Ras mutations that affect Ras activation. They performed ODE model simulation to investigate the steady-state Ras concentration response to kinetic parameter changes and found a strong correlation between oncogenic mutations and Ras activation level.…”

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confidence: 99%

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Mutation-induced protein interaction kinetics changes affect apoptotic network dynamic properties and facilitate oncogenesis

Zhao

Sun

Pei

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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It has been a consensus in cancer research that cancer is a disease caused primarily by genomic alterations, especially somatic mutations. However, the mechanism of mutation-induced oncogenesis is not fully understood. Here, we used the mitochondrial apoptotic pathway as a case study and performed a systematic analysis of integrating pathway dynamics with protein interaction kinetics to quantitatively investigate the causal molecular mechanism of mutation-induced oncogenesis. A mathematical model of the regulatory network was constructed to establish the functional role of dynamic bifurcation in the apoptotic process. The oncogenic mutation enrichment of each of the protein functional domains involved was found strongly correlated with the parameter sensitivity of the bifurcation point. We further dissected the causal mechanism underlying this correlation by evaluating the mutational influence on protein interaction kinetics using molecular dynamics simulation. We analyzed 29 matched mutant-wild-type and 16 matched SNP-wild-type protein systems. We found that the binding kinetics changes reflected by the changes of free energy changes induced by protein interaction mutations, which induce variations in the sensitive parameters of the bifurcation point, were a major cause of apoptosis pathway dysfunction, and mutations involved in sensitive interaction domains show high oncogenic potential. Our analysis provided a molecular basis for connecting protein mutations, protein interaction kinetics, network dynamics properties, and physiological function of a regulatory network. These insights provide a framework for coupling mutation genotype to tumorigenesis phenotype and help elucidate the logic of cancer initiation.mutation-induced oncogenesis | dynamic bifurcation | parameter sensitivity analysis | mutation enrichment | protein interaction kinetics H igh-throughput whole-genome sequencing (1) and massively parallel technologies (2) have enabled cancer researchers to understand that cancer is a disease caused primarily by genomic alterations, especially somatic cell mutations (3, 4). This stimulated extensive research endeavors to identify the landscape of cancer-related mutations. In the last decade, studies of different tumor types using cancer genomic and pathology analysis indicate that oncogenic mutations are concentrated primarily in a few core regulatory pathways that govern cell phenotypic behaviors (5-8). These results led to the idea that "genetic aberrations alter normal cellular regulation and then drive tumor development" (9, 10). Therefore, mutation-induced oncogenesis should be explored from a network and system perspective.A systematic interpretation of oncogenesis can be achieved in part by analyzing interactions among mutated genes and performing functional annotation of cancer-related proteins in functional pathways. A more quantitative approach is network modeling using ordinary differential equations (ODEs) and mathematical simulations. This well-established method has been successfully used to ...

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Network Analysis of Oncogenic Ras Activation in Cancer

Cited by 113 publications

References 19 publications

CNK1 Promotes Invasion of Cancer Cells through NF-κB–Dependent Signaling

CNK1 Promotes Invasion of Cancer Cells through NF-κB–Dependent Signaling

Calcium participates in feedback regulation of the oscillating ROP1 Rho GTPase in pollen tubes

Mutation-induced protein interaction kinetics changes affect apoptotic network dynamic properties and facilitate oncogenesis

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