PRICKLE1 Contributes to Cancer Cell Dissemination through Its Interaction with mTORC2

Daulat, Avais M.; Bertucci, François; Audebert, Stéphane; Sergé, Arnauld; Finetti, Pascal; Josselin, Emmanuelle; Castellano, Rémy; Birnbaum, Daniel; Angers, Stéphane; Borg, Jean-Paul

doi:10.1016/j.devcel.2016.04.011

Cited by 61 publications

(88 citation statements)

References 56 publications

(11 reference statements)

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“…For example, small interfering RNA (siRNA)-mediated Rictor knockdown has been shown to inhibit MCF7 (luminal) and MDA-MB-231 (basal-like) breast cancer cell migration [10, 11]. Rictor knockdown inhibits transforming growth factor beta (TGFβ)-mediated epithelial-to-mesenchymal transition (EMT) in basal-like breast cancer lines [12], and Prickle-dependent cell motility in the MDA-MB-231 model of breast cancer [13]. Additionally, mTOR-independent roles for Rictor in cancer cell migration have also been described.…”

Section: Introductionmentioning

confidence: 99%

Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis

et al. 2017

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BackgroundThe importance of the mTOR complex 2 (mTORC2) signaling complex in tumor progression is becoming increasingly recognized. HER2-amplified breast cancers use Rictor/mTORC2 signaling to drive tumor formation, tumor cell survival and resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapy. Cell motility, a key step in the metastatic process, can be activated by mTORC2 in luminal and triple negative breast cancer cell lines, but its role in promoting metastases from HER2-amplified breast cancers is not yet clear.MethodsBecause Rictor is an obligate cofactor of mTORC2, we genetically engineered Rictor ablation or overexpression in mouse and human HER2-amplified breast cancer models for modulation of mTORC2 activity. Signaling through mTORC2-dependent pathways was also manipulated using pharmacological inhibitors of mTOR, Akt, and Rac. Signaling was assessed by western analysis and biochemical pull-down assays specific for Rac-GTP and for active Rac guanine nucleotide exchange factors (GEFs). Metastases were assessed from spontaneous tumors and from intravenously delivered tumor cells. Motility and invasion of cells was assessed using Matrigel-coated transwell assays.ResultsWe found that Rictor ablation potently impaired, while Rictor overexpression increased, metastasis in spontaneous and intravenously seeded models of HER2-overexpressing breast cancers. Additionally, migration and invasion of HER2-amplified human breast cancer cells was diminished in the absence of Rictor, or upon pharmacological mTOR kinase inhibition. Active Rac1 was required for Rictor-dependent invasion and motility, which rescued invasion/motility in Rictor depleted cells. Rictor/mTORC2-dependent dampening of the endogenous Rac1 inhibitor RhoGDI2, a factor that correlated directly with increased overall survival in HER2-amplified breast cancer patients, promoted Rac1 activity and tumor cell invasion/migration. The mTORC2 substrate Akt did not affect RhoGDI2 dampening, but partially increased Rac1 activity through the Rac-GEF Tiam1, thus partially rescuing cell invasion/motility. The mTORC2 effector protein kinase C (PKC)α did rescue Rictor-mediated RhoGDI2 downregulation, partially rescuing Rac-guanosine triphosphate (GTP) and migration/motility.ConclusionThese findings suggest that mTORC2 uses two coordinated pathways to activate cell invasion/motility, both of which converge on Rac1. Akt signaling activates Rac1 through the Rac-GEF Tiam1, while PKC signaling dampens expression of the endogenous Rac1 inhibitor, RhoGDI2.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0868-8) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis

et al. 2017

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“…It has been reported that Prickle1 activates AKT to regulate focal adhesion turnover and promotes breast cancer cell migration through the interaction with the mammalian target of rapamycin complex 2 (mTORC2) (Daulat et al, 2016). Upregulation of Prickle1 in basal breast cancers is correlated with poor prognosis, suggesting that Prickle1 has tumor progressive functions in vivo.…”

Section: Parsons and Parsonsmentioning

confidence: 99%

Prickle1 promotes focal adhesion disassembly in cooperation with CLASP-LL5β complex in migrating cells

Lim

Matsumoto

Yamamoto

et al. 2016

Journal of Cell Science

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Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.

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“…PRICKLE1 is an evolutionary conserved cytoplasmic protein and contains from the amino-terminal end a PET followed by three LIM domains and a C-terminal farnesylation site 8 . Recently, we and others have demonstrated the prominent role of PRICKLE1 during cancer progression 2, 9–11 . PRICKLE1 is a prometastatic molecule and regulates oriented cell migration in various cell lines including the MDA-MB-231 prototypal TNBC cell line 2, 10 .…”

Section: Introductionmentioning

confidence: 95%

“…However, TNBC is highly invasive with strong metastatic propensity 1 . We recently identified PRICKLE1 as poor-prognosis marker in breast cancer 2 . PRICKLE1 is a member of a conserved group of proteins involved in planar cell polarity (PCP) pathway 3 .…”

Section: Introductionmentioning

confidence: 99%

“…PRICKLE1 is a prometastatic molecule and regulates oriented cell migration in various cell lines including the MDA-MB-231 prototypal TNBC cell line 2, 10 . At the molecular level, PRICKLE1 regulates subcellular localization of its associated proteins such as VANGL2 8, 12 , RICTOR 2 , ARHGAP22/24 10 , and LL5β 11 in order to coordinate oriented cellular migration.…”

Section: Introductionmentioning

confidence: 99%

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ECT2 associated to PRICKLE1 are poor-prognosis markers in triple-negative breast cancer

Daulat

Finetti

Revinski

et al. 2018

Preprint

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BackgroundTriple-negative breast cancers are poor-prognosis tumors characterized by absence of molecular signature and are chemotherapy is still the only systemic treatment. Currently, research focus to identify biomarkers that may be usable for prognosis and/or for treatment, notably among the proteins involved in cell migration and metastatic capacity.MethodsWe used proteomic approach to identify protein complexes associated to PRICKLE1 and the mRNA expression level of the corresponding genes in a retrospective series of 8,982 clinically annotated patients with invasive primary breast cancer were assessed. Then, we characterize molecularly the interaction between PRICKLE1 and the guanine nucleotide exchange factor ECT2. Finally, experiments in Xenopus have been carrying out to determine their evolutionary conserved interaction.ResultsWe have identified a network of proteins interacting with the prometastatic scaffold protein PRICKLE1 that includes several small G-protein regulators involved in cell migration and metastasis. Combined analysis expression of PRICKLE1 and small G-protein regulators expression has a strong prognostic value in TNBC. We show that PRICKLE1 controls the activity of ECT2 on RAC1 signaling, a pathway required for cancer cell dissemination.ConclusionsThis work supports the idea that promigratory proteins, which are overexpressed in cancerous epithelium, are suitable pharmaceutical targets.

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PRICKLE1 Contributes to Cancer Cell Dissemination through Its Interaction with mTORC2

Cited by 61 publications

References 56 publications

Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis

Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis

Prickle1 promotes focal adhesion disassembly in cooperation with CLASP-LL5β complex in migrating cells

ECT2 associated to PRICKLE1 are poor-prognosis markers in triple-negative breast cancer

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