The lipid-transfer protein Nir2 enhances epithelial-mesenchymal transition and facilitates breast cancer metastasis

Keinan, Omer; Kedan, Amir; Gavert, Nancy; Selitrennik, Michael; Kim, SoHui; Karn, Thomas; Becker, Sven; Lev, Sima

doi:10.1242/jcs.155721

Cited by 29 publications

(33 citation statements)

References 48 publications

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“…Formalin-fixed paraffin-embedded TNBC sections were processed for IHC as described previously (12). The intensity of the immunohistochemical staining was evaluated semiquantitatively and H-Score was calculated for each sample essentially as we described previously (20). Further experimental details are described in Supplementary Information.…”

Section: Immunohistochemical Staining and Analysismentioning

confidence: 99%

Targeting of PYK2 Synergizes with EGFR Antagonists in Basal-like TNBC and Circumvents HER3-Associated Resistance via the NEDD4–NDRG1 Axis

et al. 2017

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Triple-negative breast cancer (TNBC) is a highly aggressive, heterogeneous disease with poor prognosis and no effective targeted therapies. EGFR is highly expressed in basal-like TNBC and is considered as a potential therapeutic target. However, EGFR targeting exerts only marginal clinical benefits, possibly due to activation of compensatory signaling pathways, which are frequently associated with HER3 upregulation. Here we show that concomitant targeting of EGFR and the nonreceptor tyrosine kinases PYK2/FAK synergistically inhibits the proliferation of basal-like TNBC cells in vitro and attenuates tumor growth in a mouse xenograft model. Dual targeting of EGFR and PYK2/FAK inhibited complementary key growth and survival pathways mediated by AKT, S6K, STAT3, and ERK1/2 activation. PYK2 inhibition also abrogated HER3 upregulation in response to EGFR antagonists, thereby circumventing HER3-associated drug resistance. Mechanistically, PYK2 inhibition facilitated the proteasomal degradation of HER3 while inducing upregulation of NDRG1 (N-myc downstream regulated 1 gene). NDRG1 enhanced the interaction of HER3 with the ubiquitin ligase NEDD4, while PYK2, which interacts with NEDD4 and HER3, interfered with NEDD4-HER3 binding, suggesting that the PYK2-NDRG1-NEDD4 circuit has a critical role in receptor degradation, drug response, and resistance mechanism. Our studies offer a preclinical proof of concept for a strategy of cotargeting the EGFR and PYK2/FAK kinases to improve TNBC therapy. Cancer Res; 77(1); 86-99. ©2016 AACR.

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Section: Immunohistochemical Staining and Analysismentioning

confidence: 99%

Targeting of PYK2 Synergizes with EGFR Antagonists in Basal-like TNBC and Circumvents HER3-Associated Resistance via the NEDD4–NDRG1 Axis

et al. 2017

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“…The intensity of specific staining was characterized as negative (0), low (1 þ ), moderate (2 þ ) and high (3 þ ). For each sample, H-Score was calculated as described elsewhere 68 . Tumour grade was evaluated according to clinical and pathological data.…”

Section: Methodsmentioning

confidence: 99%

PYK2 sustains endosomal-derived receptor signalling and enhances epithelial-to-mesenchymal transition

et al. 2015

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Epithelial-to-mesenchymal transition (EMT) is a central developmental process implicated in cancer metastasis. Here we show that the tyrosine kinase PYK2 enhances cell migration and invasion and potentiates EMT in human breast carcinoma. EMT inducer, such as EGF, induces rapid phosphorylation of PYK2 and its translocation to early endosomes where it co-localizes with EGFR and sustains its downstream signals. Furthermore, PYK2 enhances EGF-induced STAT3-phosphorylation, while phospho-STAT3 directly binds to PYK2 promoter and regulates PYK2 transcription. STAT3 and PYK2 also enhance c-Met expression, while c-Met augments their phosphorylation, suggesting a positive feedback loop between PYK2-STAT3-c-Met. We propose that PYK2 sustains endosomal-derived receptor signalling and participates in a positive feedback that links cell surface receptor(s) to transcription factor(s) activation, thereby prolonging signalling duration and potentiating EMT. Given the role of EMT in breast cancer metastasis, we also found a significant correlation between PYK2 expression, tumour grade and lymph node metastasis, thus, demonstrating the clinicopathological implication of our findings.

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“…Thus, Nir2 and Nir3 are feedback regulators for PM PIP 2 homeostasis by detecting metabolic intermediates generated by PIP 2 hydrolysis, translocating to ER-PM junctions, and replenishing PM PIP 2 [150, 151]. Consistently, knockdown of Nir2 significantly affected PIP 2 -associated functions, including receptor-induced Ca 2+ signaling, epidermal growth factor (EGF) signaling, cell migration, and epithelial-mesenchymal transition (EMT) [146, 147, 152]. …”

Section: Recent Advances In Understanding the Regulation And Functmentioning

confidence: 99%

ER-plasma membrane junctions: Why and how do we study them?

Chang

Chen

Liou

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are membrane microdomains important for communication between the ER and the PM. ER-PM junctions were first reported in muscle cells in 1957, but mostly ignored in non-excitable cells due to their scarcity and lack of functional significance. In 2005, the discovery of stromal interaction molecule 1 (STIM1) mediating a universal Ca2+ feedback mechanism at ER-PM junctions in mammalian cells led to a resurgence of research interests toward ER-PM junctions. In the past decade, several major advancements have been made in this emerging topic in cell biology, including the generation of tools for labeling ER-PM junctions and the unraveling of mechanisms underlying regulation and functions of ER-PM junctions. This review summarizes early studies, recently developed tools, and current advances in the characterization and understanding of ER-PM junctions. This article is part of a Special Issue entitled: Membrane contact sites edited by Benoit Kornmann and Christian Ungermann.

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The lipid-transfer protein Nir2 enhances epithelial-mesenchymal transition and facilitates breast cancer metastasis

Cited by 29 publications

References 48 publications

Targeting of PYK2 Synergizes with EGFR Antagonists in Basal-like TNBC and Circumvents HER3-Associated Resistance via the NEDD4–NDRG1 Axis

Targeting of PYK2 Synergizes with EGFR Antagonists in Basal-like TNBC and Circumvents HER3-Associated Resistance via the NEDD4–NDRG1 Axis

PYK2 sustains endosomal-derived receptor signalling and enhances epithelial-to-mesenchymal transition

ER-plasma membrane junctions: Why and how do we study them?

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