K-Ras4B proteins are expressed in the nucleolus: Interaction with nucleolin

Birchenall-Roberts, Maria C.; Fu, Tao; Kim, Soo-Gyung; Huang, Ying; Dambach, Michael; Resau, James H.; Ruscetti, Francis W.

doi:10.1016/j.bbrc.2006.07.094

Cited by 16 publications

(18 citation statements)

References 35 publications

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“…Intriguingly, nucleolin has also recently been shown to interact with the cytoplasmic domain of ERB4 receptors (38), which is consistent with our observation of nucleolin on the inner plasma membrane. In addition, a previous study demonstrates an interaction between K-Ras and nucleolin (39). However, in contrast to our data, this study concluded the K-Ras-nucleolin interaction was nucleolar.…”

Section: Discussioncontrasting

confidence: 56%

Nucleophosmin and Nucleolin Regulate K-Ras Plasma Membrane Interactions and MAPK Signal Transduction

Inder

Lau

Loo

et al. 2009

Journal of Biological Chemistry

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The spatial organization of Ras proteins into nanoclusters on the inner leaflet of the plasma membrane is essential for high fidelity signaling through the MAPK pathway. Here we identify two selective regulators of K-Ras nanoclustering from a proteomic screen for K-Ras interacting proteins. Nucleophosmin (NPM) and nucleolin are predominantly localized to the nucleolus but also have extranuclear functions. We show that a subset of NPM and nucleolin localizes to the inner leaflet of plasma membrane and forms specific complexes with K-Ras but not other Ras isoforms. Active GTPloaded and inactive GDP-loaded K-Ras both interact with NPM, although NPM-K-Ras binding is increased by growth factor receptor activation. NPM and nucleolin both stabilize K-Ras levels on the plasma membrane, but NPM concurrently increases the clustered fraction of GTP-K-Ras. The increase in nanoclustered GTP-K-Ras in turn enhances signal gain in the MAPK pathway. In summary these results reveal novel extranucleolar functions for NPM and nucleolin as regulators of K-Ras nanocluster formation and activation of the MAPK pathway. The study also identifies a new class of K-Ras nanocluster regulator that operates independently of the structural scaffold galectin-3.

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Section: Discussioncontrasting

confidence: 56%

Nucleophosmin and Nucleolin Regulate K-Ras Plasma Membrane Interactions and MAPK Signal Transduction

Inder

Lau

Loo

et al. 2009

Journal of Biological Chemistry

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“…It was proposed that K-ras 4B isoform formed complex with nucleolin to co-localize in to the nucleus [71]. This study also reported the absence of H-ras and K-ras 4A expression in nucleus, also concerning the fact that inhibition of K-ras 4B-nucleolin complex prevented the transport of K-ras 4B into the nucleus.…”

Section: Nuclear Localization Of Rassupporting

confidence: 71%

Ras and Ras mutations in cancer

Rajasekharan

Raman

2013

Open Life Sciences

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Ras genes are pre-eminent genes that are frequently linked with cancer biology. The functional loss of ras protein caused by various point mutations within the gene, is established as a prognostic factor for the genesis of a constitutively active Ras-MAPK pathway leading to cancer. Ras signaling circuit follows a complex pathway, which connects many signaling molecules and cells. Several strategies have come up for targeting mutant ras proteins for cancer therapy, however, the clinical benefits remain insignificant. Targeting the Ras-MAPK pathway is extremely complicated due its intricate networks involving several upstream and downstream regulators. Blocking oncogenic Ras is still in latent stage and requires alternative approaches to screen the genes involved in Ras transformation. Understanding the mechanism of Ras induced tumorigenesis in diverse cancers and signaling networks will open a path for drug development and other therapeutic approaches.

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“…Because all 3 interact with nucleolin, it is reasonable to assume that the Cterminal farnesylcysteine and/or the domains upstream of the hvr that they share in common may be involved in nucleolinRas interactions. Nucleolin was reported previously to interact with K-Ras4B but not with H-Ras in the nucleolus (32). In a study published during the final preparation of our manuscript, it was reported that nucleolin from postnuclear supernatants of BHK cells interacts with K-Ras but not with H-Ras (43).…”

Section: Discussionmentioning

confidence: 66%

“…This key protein is involved in various aspects of ribosome biogenesis, from transcriptional regulation to the assembly of preribosomal particles. One study described interactions between nucleolin and K-Ras in the nucleolus (32). Other reports suggest that it could also play an important role in nonnucleolar functions (14).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Synergism between ErbB1, Nucleolin, and Mutant Ras

et al. 2011

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Alterations in the ErbB family of growth factor receptors, their signaling components, and mutational activation of Ras proteins are major contributors to malignant transformation. Recently, mutant Ras was shown to be capable of activating ErbB receptors in a ligand-independent manner. Furthermore, it was observed that nucleolin, a transcriptional regulator and ribosome biogenesis factor, can bind both K-Ras and the cytoplasmic tail of ErbB receptors to enhance ErbB receptor activation. However, the functional significance of these interactions to cancer pathogenesis has not been probed. Here, we show that endogenous nucleolin interacts simultaneously in vivo with endogenous Ras and ErbB1 (EGFR) in cancer cells. The C-terminal 212 amino acids of nucleolin were determined to be sufficient to interact with ErbB1 and all Ras protein isoforms (H-, N-, and KRas). Nucleolin partially colocalizes with Ras at the plasma membrane. Moreover, activated but not wild-type Ras facilitates nucleolin interaction with ErbB1 and stabilizes ErbB1 receptor levels. Most importantly, these three oncogenes synergistically facilitate anchorage-independent cell growth in vitro and tumor growth in vivo. Our findings suggest strategies to target nucleolin as a general approach to inhibiting ErbB-and Ras-driven cancers. Cancer Res; 71(6); 2140-51. Ó2011 AACR.

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K-Ras4B proteins are expressed in the nucleolus: Interaction with nucleolin

Cited by 16 publications

References 35 publications

Nucleophosmin and Nucleolin Regulate K-Ras Plasma Membrane Interactions and MAPK Signal Transduction

Nucleophosmin and Nucleolin Regulate K-Ras Plasma Membrane Interactions and MAPK Signal Transduction

Ras and Ras mutations in cancer

Oncogenic Synergism between ErbB1, Nucleolin, and Mutant Ras

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