Regulation of the Src-PP2A Interaction in Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis

Xu, Jing; Xu, Zhengfan; Zhou, Jun; Zhuang, Zhengping; Wang, Enhua; Boerner, Julie L.; Wu, Gen Sheng

doi:10.1074/jbc.m113.508093

Cited by 22 publications

(21 citation statements)

References 38 publications

(32 reference statements)

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“…LB-102 inhibits PP2A to increase the efficacy of drugs, including doxorubicin, in xenograph animal models of glioblastoma by blocking cellular DNA damage defence mechanisms that are targeted by the chemotherapeutic agent [37]. The related PP2A inhibitor, LB-100 (currently in clinical trials; NCT01837667 [56]), similarly enhances chemo-sensitivity to drugs in a number of cancer cell types, including sarcoma [57], pheochromocytoma [58], nasopharyngeal carcinoma [59], hepatocellular carcinoma [60], medulloblastoma [61] and pancreatic cancer [62,63] as well as both breast [64] and ovarian cancers [65].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Cancer cells with elevated Src signaling and high expression levels of CXCR4 (the receptor for CXCL12) are especially primed to utilize the physiological survival signals in the bone marrow, increasing the probability of establishing overt metastasis later on [21, 26]. In addition, high Src activity has been shown to counteract pro-apoptotic signaling of TRAIL, a cytokine also present in bone metastatic lesions [21, 44]. These findings from animal models are also reflected in clinical datasets in which CXCR4 expression and expression of the Src signature in tumor cells is associated with breast cancer bone relapse [21].…”

Section: The Final Stage Of the Metastatic Cascade: Organ Colonizationmentioning

confidence: 99%

Surviving at a Distance: Organ-Specific Metastasis

2015

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The clinical manifestation of metastasis in a vital organ is the final stage of cancer progression and the main culprit of cancer related mortality. Once established, metastasis is devastating, yet only a small proportion of the cancer cells that leave a tumor succeed at infiltrating, surviving, and ultimately overtaking a distant organ. The bottlenecks that challenge cancer cells in newly invaded microenvironments are organ specific and consequently demand distinct mechanisms for metastatic colonization. Here we review the metastatic traits that allow cancer cells to colonize distinct organ sites.

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“…MYC-pCMV6M-PAK1 WT and PAK1 K299R (Addgene plasmids 12209 and 12210) and His 6 -pET28-PAK2 WT were gifts from Jonathan Chernoff (42). The catalytic subunit of PP2A (pcDNA-PP2A/C-HA) was a gift from Gen Sheng Wu (43). pGEX encoding GST-tagged Rac1 was a gift from Katrin Rittinger.…”

Section: Methodsmentioning

confidence: 99%

p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase

Barrows

Schoenfeld

Hodakoski

et al. 2015

Journal of Biological Chemistry

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Background:The role of phosphorylation for regulating the Rac1 GEF PREX2 is not understood. Results: PAK phosphorylation of PREX2 downstream of PIP 3 and G␤␥ reduces PREX2 GEF activity. Conclusion: Second messengers can initiate negative feedback to decrease Rac1 activation through PAK phosphorylation of PREX2. Significance: PAK negative regulation of GEFs could represent a broadly utilized mechanism to attenuate Rac1 activation and its outputs.

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Regulation of the Src-PP2A Interaction in Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis

Cited by 22 publications

References 38 publications

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

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

Surviving at a Distance: Organ-Specific Metastasis

p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase

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