RACK1 Promotes Non-small-cell Lung Cancer Tumorigenicity through Activating Sonic Hedgehog Signaling Pathway

Shi, Shuo; Deng, Yuezhen; Zhao, Jiang-Sha; Ji, Xiaodong; Shi, Jun; Feng, Yuxiong; Li, Guo; Li, Jingjing; Zhu, Di; Koeffler, H. Phillip; Zhao, Yun; Xie, Dong

doi:10.1074/jbc.m111.315416

Cited by 79 publications

(78 citation statements)

References 54 publications

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“…Western blot analysis and immunoprecipitation were performed as described previously [17]. Details were available in Supplementary information, Data S1.…”

Section: Western Blot Analysis and Immunoprecipitationmentioning

confidence: 99%

“…Due to its interaction with a range of signaling proteins, such as PKC, Src and IFNα receptor, RACK1 has been widely perceived as an indispensable hub for signaling transduction in multiple signaling pathways [17][18][19][20][21][22]. Previous studies have demonstrated that RACK1 plays an important role in regulating cell growth, apoptosis and mobility [23,24].…”

Section: Introductionmentioning

confidence: 99%

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RACK1 modulates NF-κB activation by interfering with the interaction between TRAF2 and the IKK complex

Long

Deng

et al. 2013

Cell Res

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Abbreviations: RACK1 (receptor for activated C kinase 1); NF-κB (nuclear factor kappa-B); TNF-α (tumor necrosis factor-alpha); IKK (inhibitor of nuclear factor kappa-B kinase); IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha); TRAF2 (TNF receptor-associated factor 2); JNK (JUN N-terminal kinase); RIP1 (receptor The transcription factor NF-κB plays a pivotal role in innate immunity in response to a variety of stimuli, and the coordinated regulation of this pathway determines the proper host responses to extracellular signals. In this study, we identified RACK1 as a novel negative regulator of NF-κB signaling, NF-κB-mediated cytokine induction and inflammatory reactions. RACK1 physically associates with the IKK complex in a TNF-triggered manner. This interaction interferes with the recruitment of the IKK complex to TRAF2, which is a critical step for IKK phosphorylation and subsequent activation triggered by TNF. By modulating the interaction between TRAF2 and IKK, RACK1 regulates the levels of NF-κB activation in response to different intensities of stimuli. Our findings suggest that RACK1 plays an important role in controlling the sensitivity of TNF-triggered NF-κB signaling by regulating IKK activation and provide new insight into the negative regulation of inflammatory reactions.

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“…Western blot analysis and immunoprecipitation were performed as described previously [17]. Details were available in Supplementary information, Data S1.…”

Section: Western Blot Analysis and Immunoprecipitationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

RACK1 modulates NF-κB activation by interfering with the interaction between TRAF2 and the IKK complex

Long

Deng

et al. 2013

Cell Res

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“…RACK1 is also a component of the signalling pathways downstream of FAK and phosphodiesterase 4D5 (PDE4D5) that control both cell spreading and the direction sensing mechanisms required to establish cell polarity, which is an important element in the process of cell migration [14,15]. RACK1 has also been shown to promote both cell migration and invasion in both oesophageal and lung cancers through a variety of different signalling mechanisms [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

Kiely

Adams

Hayes

et al. 2017

Cellular Signalling

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. (2017) RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells. Cellular Signalling, 35, pp. 290-300. (doi:10.1016Signalling, 35, pp. 290-300. (doi:10. /j.cellsig.2016 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/128660/ RACK1/PP2A complex is required for cell adhesion, proliferation, migration, invasion.Potential role for the RACK1/PP2A complex in the progression of breast cancer. KeywordsBreast Cancer, RACK1, PP2A, Protein-Protein Interactions. ABSTRACTConflicting reports implicate the scaffolding protein RACK1 in the progression of breast cancer. RACK1 has been identified as a key regulator downstream of growth factor and adhesion signalling and as a direct binding partner of PP2A. Our objective was to further characterise the interaction between PP2A and RACK1 and to advance our understanding of this complex in breast cancer cells. We examined how the PP2A holoenzyme is assembled on the RACK1 scaffold in MCF-7 cells. We used immobilized peptide arrays representing the entire PP2A-catalytic subunit to identify candidate amino acids on the C subunit of PP2A that might be involved in binding of RACK1. We identified the RACK1 interaction sites on PP2A. Stable cell lines expressing PP2A with FR69/70AA, R214A and Y218F substitutions were generated and it was confirmed that the RACK1/PP2A interaction is essential to stabilize PP2A activity. We used Real-Time Cell Analysis and a series of assays to demonstrate that disruption of the RACK1/PP2A complex also reduces the adhesion, proliferation, migration and invasion of breast cancer cells and plays a role in maintenance of the cancer phenotype. This work has significantly advanced our understanding of the RACK1/PP2A complex and suggests a pro-carcinogenic role for the RACK1/PP2A interaction. This work suggests that approaches to target the RACK1/PP2A complex are a viable option to regulate PP2A activity and identifies a novel potential therapeutic target in the treatment of breast cancer.

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“…Our results also suggest that inhibitors of RACK1 could be useful to prevent adverse renal effects of DPPIV inhibitors, could be antihypertensive, and could prevent or treat hypertension-induced or diabetesinduced nephropathy. Finally, some studies implicate RACK1 in the pathology of cancer (31,41,48), and a recent analysis suggests that patients with hypertension are at increased risk of cancer (51). It is conceivable, although speculative, that inhibitors of RACK1 could prevent the adverse effects of DPPIV inhibitors, could lower arterial blood pressure, and could decrease the risk of cancer.…”

Section: Discussionmentioning

confidence: 99%

Role of RACK1 in the differential proliferative effects of neuropeptide Y_1–36 and peptide YY_1–36 in SHR vs. WKY preglomerular vascular smooth muscle cells

Cheng

Zhu

Gillespie

et al. 2013

American Journal of Physiology-Renal Physiology

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Cheng D, Zhu X, Gillespie DG, Jackson EK. Role of RACK1 in the differential proliferative effects of neuropeptide Y 1-36 and peptide YY and PYY1-36 stimulated proliferation. In SHR PGVSMCs, inhibitors of the G i/phospholipase C/PKC pathway (a pathway known to be organized by RACK1) attenuated the ability of NPY 1-36 to stimulate the proliferation of SHR PGVSMCs. Our results suggest that RACK1 modulates the ability of PGVSMCs to respond to the proliferative actions of NPY 1-36 and PYY1-36 and differences in RACK1 levels/ localization account for, in part, differential proliferative responses to NPY 1-36 and PYY1-36 in SHR vs. WKY PGVSMCs. Because dipeptidyl peptidase IV inhibitors increase NPY 1-36 and PYY1-36 levels, our findings have implications for the use of such drugs in diabetic patients.receptor for activated C kinase 1; cell proliferation; preglomerular vascular smooth muscle cells; spontaneously hypertensive rats; WistarKyoto rats NEUROPEPTIDE Y1-36 (NPY1-36) and peptide YY 1-36 (PYY 1-36 ) are members of the pancreatic polypeptide-fold (PP-fold) family (6). Importantly, the kidney is likely exposed to biologically active levels of PP-fold peptides because 1) renal sympathetic varicosities release NPY 1-36 in response to CNS-mediated activation of renal sympathetic nerves (13); 2) NPY 1-36 is made by renal epithelial cells and released into the renal interstitium (22); and 3) fatty meals stimulate endocrine L-cells in the GI tract to release PYY 1-36 into the systemic circulation, producing physiologically active levels of PYY 1-36 in plasma (3,4,19,28,34,44,53), and this PYY 1-36 would be promptly delivered to the kidney via the bloodstream.The exposure of the kidney to pharmacologically active levels of NPY 1-36 or PYY 1-36 may have implications for renovascular structure and health. In this regard, our recent experiments indicate that both NPY 1-36 and PYY 1-36 stimulate the proliferation of preglomerular microvascular smooth muscle cells (PGVSMCs) obtained from spontaneously hypertensive rats (SHR) via a mechanism involving activation of Y 1 receptors (26). In contrast, NPY 1-36 and PYY 1-36 exert little or no effect on proliferation of PGVSMCs obtained from normotensive Wistar-Kyoto rats (WKY). Thus, endogenous PP-fold peptides may have adverse effects on renovascular structure in genetic hypertension. However, the reason that NPY 1-36 and PYY 1-36 robustly stimulate proliferation of PGVSMCs only in PGVSMCs obtained from genetically susceptible kidneys is unclear. Thus, the focus of the current study was to investigate why SHR, but not WKY, PGVSMCs are responsive to the proliferative effects of NPY 1-36 and PYY 1-36 .Our previously published work demonstrates that Y 1 receptor expression is not different in preglomerular microvessels from SHR vs. WKY (15), so receptor expression differences are unlikely to account for the differential proliferative responses of SHR vs. WKY to NPY 1-36 and PYY . On the other hand, our previously published work does show that signaling via G i -linked receptors is...

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RACK1 Promotes Non-small-cell Lung Cancer Tumorigenicity through Activating Sonic Hedgehog Signaling Pathway

Cited by 79 publications

References 54 publications

RACK1 modulates NF-κB activation by interfering with the interaction between TRAF2 and the IKK complex

RACK1 modulates NF-κB activation by interfering with the interaction between TRAF2 and the IKK complex

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

Role of RACK1 in the differential proliferative effects of neuropeptide Y_1–36 and peptide YY_1–36 in SHR vs. WKY preglomerular vascular smooth muscle cells

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RACK1 Promotes Non-small-cell Lung Cancer Tumorigenicity through Activating Sonic Hedgehog Signaling Pathway

Cited by 79 publications

References 54 publications

RACK1 modulates NF-κB activation by interfering with the interaction between TRAF2 and the IKK complex

RACK1 modulates NF-κB activation by interfering with the interaction between TRAF2 and the IKK complex

RACK1 stabilises the activity of PP2A to regulate the transformed phenotype in mammary epithelial cells

Role of RACK1 in the differential proliferative effects of neuropeptide Y1–36 and peptide YY1–36 in SHR vs. WKY preglomerular vascular smooth muscle cells

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Role of RACK1 in the differential proliferative effects of neuropeptide Y_1–36 and peptide YY_1–36 in SHR vs. WKY preglomerular vascular smooth muscle cells