Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation

Yamaguchi, Hideki; Yoshida, Shuhei; Muroi, Emi; Yoshida, Nachi; Kawamura, Masahiro; Kouchi, Zen; Nakamura, Yoshikazu; Sakai, Ryuichi; Fukami, Kiyoko

doi:10.1083/jcb.201009126

Cited by 120 publications

(126 citation statements)

References 67 publications

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“…Formation of invadopodia in cancer cells or podosomes in Srctransformed fibroblasts requires activation of Smads and PI3K (76)(77)(78)(79). In this work, we showed that pharmacological inhibition of PI3K blocked invadosome-mediated ECM degradation in RA synoviocytes or in cells stimulated with PDGF.…”

Section: Discussionmentioning

confidence: 53%

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

Charbonneau

Lavoie

Lauzier

et al. 2016

The Journal of Immunology

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Fibroblast-like synoviocytes (FLS) play a major role in invasive joint destruction in rheumatoid arthritis (RA). This prodestructive phenotype has been shown to involve autocrine TGF-β that triggers formation of matrix-degrading invadosomes through molecular mechanisms that are not fully elucidated. The platelet-derived growth factor (PDGF) receptor (PDGFR) family of receptor tyrosine kinases (RTK) has been shown to cooperate with TGF-β in various pathological conditions. We therefore sought to determine whether RTK activity played a role in invadosome biogenesis. We demonstrated that, among the common RTKs, PDGFR-αβ was specifically phosphorylated in FLS from RA patients. Phosphorylation of PDGFR-αβ was also elevated in RA synovial tissues. Interference with PDGFR activation or PDGF neutralization inhibited invadosome formation in RA synoviocytes, indicating the presence of an autocrine PDGFR activation loop that involved endogenous PDGF. Among the PDGF-A–D isoforms, only PDGF-B was found both significantly elevated in FLS lines from RA patients, and related to high-invadosome forming cells. Addition of TGF-β upregulated invadosome formation, PDGF-B mRNA expression, and phosphorylation of PDGFR. All of these functions were efficiently suppressed by TGF-β neutralization or interference with the Smad/TβR1or PI3K/Akt pathway. Among the class 1 PI3K family proteins known to be expressed in RA synoviocytes, PI3Kα was selectively involved in PDGF-B expression, whereas both PI3Kα and PI3Kδ participated in invadosome formation. Our findings demonstrate that PDGFR is a critical RTK required for the prodestructive phenotype of RA synovial cells. They also provide evidence for an association between autocrine TGF-β and PDGFR-mediated invadosome formation in RA synoviocytes that involves the production of PDGF-B induced by TGF-β.

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Section: Discussionmentioning

confidence: 53%

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

Charbonneau

Lavoie

Lauzier

et al. 2016

The Journal of Immunology

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“…S4D) is unique to this mutation. Interestingly, increased PI(3,4)P 2 levels are thought to promote increased cell migration (22)(23)(24). Given these findings and our mass spectrometry data showing enrichment of cell migration processes, we hypothesized that the increased PI(3,4)P 2 levels in p.A126G would cause increased cell migration relative to PTEN loss-of-function mutations.…”

Section: Significancementioning

confidence: 83%

“…There is a statistical significance between mutant p.A126G and catalytic dead p. find that this changed enzymatic specificity causes an oncogenic increase in PI(3,4)P 2 levels at the expense of the PI(3,4,5)P 3 concentration. Up-regulation of PI(3,4)P 2 is typically associated with increased cell migration (23,24), and we are able to demonstrate, through global phospho-proteome characterization and in vitro cellular assays, that PTEN p.A126G interferes with cell proliferation pathways and likely even increases the ability of cells to migrate. Contrary to current dogma, these observations suggest that PTEN can also act as an oncogene as well as a tumor suppressor.…”

Section: Significancementioning

confidence: 86%

Discovery and functional characterization of a neomorphic PTEN mutation

Costa

Leitner

Sos

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although a variety of genetic alterations have been found across cancer types, the identification and functional characterization of candidate driver genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles. Here, we use whole genome sequencing of a prostate cancer tumor, computational analyses, and experimental validation to identify and predict novel oncogenic activity arising from a point mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor protein.We demonstrate that this mutation (p.A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphoinositide (PI) 3-phosphatase to a phosphoinositide (PI) 5-phosphatase. Using cellular assays, we demonstrate that this gain-of-function activity shifts cellular phosphoinositide levels, hyperactivates the PI3K/ Akt cell proliferation pathway, and exhibits increased cell migration beyond canonical PTEN loss-of-function mutants. These findings suggest that mutationally modified PTEN can actively contribute to welldefined hallmarks of cancer. Lastly, we demonstrate that these effects can be substantially mitigated through chemical PI3K inhibitors. These results demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy.functional genomics | PTEN | tumor suppressor

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“…Immunofluorescence was conducted as previously described (34). Briefly, the cells were fixed in 4% paraformaldehyde for 15 minutes and permeabilized with 0.1% Triton X-100 for 5 minutes.…”

Section: Immunofluorescencementioning

confidence: 99%

“…Fluorescent gelatin-coated coverslips were prepared as described previously (29,34). MDA-MB-231 and RPMI 7951 cells were cultured for 3 to 7 hours on coverslips coated with fluorescent gelatin.…”

Section: Invadopodia Assaymentioning

confidence: 99%

CDCP1 Regulates the Function of MT1-MMP and Invadopodia-Mediated Invasion of Cancer Cells

Miyazawa

Uekita

Ito

et al. 2013

Molecular Cancer Research

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Complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing protein 1 (CDCP1) is a transmembrane protein that regulates anchorage-independent growth and cancer cell migration and invasion. Expression of CDCP1 is detected in a number of cancer cell lines and tissues and is closely correlated with poor prognosis. Invadopodia are actin-based protrusions on the surface of invasive cancer cells that promote the degradation of the extracellular matrix (ECM) via localized proteolysis, which is mainly mediated by membrane type 1 matrix metalloproteinase (MT1-MMP). MT1-MMP is accumulated at invadopodia by targeted delivery via membrane trafficking. The present study shows that CDCP1 is required for ECM degradation by invadopodia in human breast cancer and melanoma cells. CDCP1 localized to caveolin-1-containing vesicular structures and lipid rafts and was detected in close proximity to invadopodia. Further biochemical analysis revealed that substantial amounts of CDCP1 existed in the Triton X-100 insoluble lipid raft fraction. CDCP1 was coimmunoprecipitated with MT1-MMP and colocalized with MT1-MMP at the vesicular structures. The siRNA-mediated knockdown of the CDCP1 expression markedly inhibited MT1-MMP-dependent ECM degradation and Matrigel invasion and reduced the accumulation of MT1-MMP at invadopodia, as shown by immunofluorescence analysis. These results indicate that CDCP1 is an essential regulator of the trafficking and function of MT1-MMP-and invadopodia-mediated invasion of cancer cells. Mol Cancer Res; 11(6); 628-37.

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Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation

Abstract: Inhibition of p110α or of the downstream PI3K signaling pathway components PDK1 and Akt, as well as phosphoinositide sequestration, blocks invadopodia formation in breast cancer cells.

Cited by 120 publications

References 67 publications

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

Discovery and functional characterization of a neomorphic PTEN mutation

CDCP1 Regulates the Function of MT1-MMP and Invadopodia-Mediated Invasion of Cancer Cells

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