p27Kip1 promotes invadopodia turnover and invasion through the regulation of the PAK1/Cortactin pathway

Jeannot, Pauline; Nowosad, Ada; Perchey, Renaud T; Callot, Caroline; Bennana, Evangéline; Katsube, Takanori; Mayeux, Patrick; Guilhot, François; Manenti, Stéphane; Besson, Arnaud

doi:10.7554/elife.22207

Cited by 48 publications

(46 citation statements)

References 100 publications

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“…A previous in vitro study has reported that PAK1 can act upstream of p27 to increase p27–cortactin interaction and PAK1‐mediated cortactin phosphorylation to promote the invasion of mouse embryonic fibroblasts (MEF) (Jeannot et al , ). However, this particular mechanism is not supported by our cytoplasmic p27 IP–MS data, where cortactin was not co‐immunoprecipitated with cytoplasmic p27 in OS cells.…”

Section: Discussionmentioning

confidence: 99%

Mislocalized cytoplasmic p27 activates PAK1‐mediated metastasis and is a prognostic factor in osteosarcoma

Chen

Cates

et al. 2020

Molecular Oncology

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The development of pulmonary metastasis is the leading cause of death in osteosarcoma (OS), which is the most common malignant bone tumor in children. We have previously reported that the tumor suppressor p27 (KIP1, CDKN1B) is frequently mislocalized to the cytoplasm of OS. However, its prognostic significance and metastatic mechanism are still elusive. Here, we show that cytoplasmic p27 significantly correlated with a higher metastatic status and poorer survival of OS patients (n = 136, P < 0.05), highlighting the clinical significance of p27 mislocalization in OS. Mechanistically, cytoplasmic p27 is co‐immunoprecipitated with p21‐activated kinase 1 (PAK1), which resulted in higher PAK1 phosphorylations, actin polymerization, and cell motility in p27‐mislocalized OS cells. Silencing PAK1 expression in different p27‐mislocalized OS cell lines decreased the migratory and adhesion abilities in vitro, as well as the development of pulmonary metastases in vivo. Similar PAK1‐dependent motility was also observed in other p27‐mislocalized cancer cell lines. In summary, our study suggests that cytoplasmic p27‐mediated PAK1 activation is crucial for OS metastasis. A biomarker‐guided targeted therapeutic approach for metastatic OS and other cancers harboring p27 mislocalization can be developed, where cytoplasmic p27 is used for risk stratification and PAK1 can be exploited as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Mislocalized cytoplasmic p27 activates PAK1‐mediated metastasis and is a prognostic factor in osteosarcoma

Chen

Cates

et al. 2020

Molecular Oncology

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“…In a recent study, p27 kip1 was shown to physically interact with cortactin and mediate its interaction with the p21-activated kinase, PAK1. PAK1 phosphorylates cortactin on S113 and thereby promotes invadopodia turnover 21 . In that work, the authors suggest that the role of p27 kip1 in invadopodia function is restricted to the cytoplasmic compartment, without any links to its cell cyclerelated function in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…Their mislocalization to the cytoplasm is associated with higher aggressiveness of several types of cancers, including breast cancer (Liang et al 2002;Roninson 2002;Shin et al 2002;Viglietto et al 2002;Winters et al 2001;Zhou et al 2001). Most recently, a study demonstrated that p27 kip1 facilitates invadopodia dynamics through the PAK1-cortactin axis (Jeannot et al 2017). Thus, further investigation is required to determine the molecular mechanism by which invadopodia-driven motility is coordinated with cell cycle progression.…”

Section: Introductionmentioning

confidence: 99%

Invadopodia degrade ECM in the G1 phase of the cell cycle

Bayarmagnai

Perrin

et al. 2018

Preprint

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Invadopodia are cancer cell protrusions rich in structural proteins (e.g. Tks5, cortactin) and proteases (e.g. MT1-MMP) and are responsible for degradation of the extracellular matrix (ECM). Tumor cell invasion and metastasis require cancer cells to be both proliferative and invasive, i.e. migrate through the tissue and assemble invadopodia.While several studies addressed how cell motility parameters change throughout the cell cycle, the relationship between invadopodia and cell cycle progression has not been elucidated. In this study, using invadopodia-and cell cycle-fluorescent markers, we show in 2D-and 3D-cell cultures, as well as in vivo, that breast carcinoma cells assemble invadopodia and invade into the surrounding ECM preferentially during the G1 phase of the cell cycle. Cells synchronized in the G0/G1 phase of the cell cycle degrade at significantly higher levels during the first 20 hours post-synchronization release. Consistent with this, mRNA and protein levels of the invadopodia core components, cortactin and MT1-MMP, peak at 14 hours post-release. We demonstrate that the cell cycle progression is faster in cells with abolished invadopodia (Tks5 knockdown, Tks5-KD), evidenced by earlier induction of cyclins A and B. Closer look at the regulators of G1 revealed that the overexpression of p27 kip1 , but not p21 cip1 , causes faster turnover of invadopodia and increased ECM degradation. Furthermore, we show that both endogenous and over-expressed p27 kip1 localize to the sites of invadopodia assembly. Taken together, these findings suggest that the invadopodia function is tightly linked to cell cycle progression and is controlled by cell cycle regulators. Our results caution that the coordination of invasion and cell cycle must be considered when designing effective chemotherapies.

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“…Recent study has shown that the cytoplasmic pool of cyclin-dependent kinase inhibitor p27 is involved in regulation of ECM degradation. 44 On a similar note, anchor cell invasion into vulval epithelium, occurring during development in C. elegans, is only performed by cells that are in G0/G1 phase of the cell cycle. 45 Tumor cell arrest during the G1/S transition, by inhibitors of Cdk4/6, is one of the new avenues for breast carcinoma treatment.…”

Section: Discussionmentioning

confidence: 99%

Directed, but not random, breast cancer cell migration is faster in the G1 phase of the cell cycle in 2D and 3D environments

et al. 2018

Preprint

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Cancer cell migration is essential for the early steps of metastasis, during which cancer cells move through the primary tumor and reach the blood vessels. In vivo, cancer cells are exposed to directional guidance cues, either soluble, such as gradients of growth factors, or insoluble, such as collagen fiber alignment. Depending on the number and strength of such cues, cells will migrate in a random or directed manner. Interestingly, similar cues also stimulate cell proliferation. In this regard, it is not clear whether cell cycle progression affects migration of cancer cells and whether this effect is different in random versus directed migration. In this study, we tested the effect of cell cycle progression on random and directed migration, both in 2D and 3D environments, in the breast carcinoma cell line, FUCCI-MDA-MB-231, using computational image analysis by LEVER. Directed migration in 2D was modeled as chemotaxis along a gradient of soluble EGF inside 10 µm-wide microchannels. In 3D, directed migration was modeled as contact guidance (alignotaxis) along aligned collagen fibers. Time-lapse recordings of cells in 2D and 3D revealed that directed, but not random migration, is cell cycle-dependent. In both 2D and 3D directed migration, cells in the G1 phase of the cell cycle outperformed cells in the G2 phase in terms of migration persistence and instantaneous velocity. These data suggest that in the presence of guidance cues in vivo, breast carcinoma cells in the G1 phase of the cell cycle may be more efficient in reaching vasculature.not peer-reviewed)

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p27Kip1 promotes invadopodia turnover and invasion through the regulation of the PAK1/Cortactin pathway

Cited by 48 publications

References 100 publications

Mislocalized cytoplasmic p27 activates PAK1‐mediated metastasis and is a prognostic factor in osteosarcoma

Mislocalized cytoplasmic p27 activates PAK1‐mediated metastasis and is a prognostic factor in osteosarcoma

Invadopodia degrade ECM in the G1 phase of the cell cycle

Directed, but not random, breast cancer cell migration is faster in the G1 phase of the cell cycle in 2D and 3D environments

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