Rnd3-induced cell rounding requires interaction with Plexin-B2

McColl, Brad; Garg, Ritu; Riou, Philippe; Riento, Kirsi; Ridley, Anne J.

doi:10.1242/jcs.192211

Cited by 21 publications

(33 citation statements)

References 52 publications

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“…The intracellular domain of PlexinB2 can elicit RhoA activation in response to ligand stimulation, through the activity of plexin-associated Rho-GEFs, such as p190-PRG and LARG [14,18,31,32]. Indeed, we observed a reduced content of F-actin stress fibers in Sema4C-or PlexinB2depleted cells compared with controls (data not shown), which could be consistent with decreased RhoA activity.…”

Section: Sema4c/plexinb2/larg-dependent Rhoa Signaling Is Required Tosupporting

confidence: 73%

Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential

Gurrapu

Pupo

Franzolin³

et al. 2018

Cell Death Differ

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Semaphorin 4C (Sema4C) expression in human breast cancers correlates with poor disease outcome. Surprisingly, upon knock-down of Sema4C or its receptor PlexinB2 in diverse mammary carcinoma cells (but not their normal counterparts), we observed dramatic growth inhibition associated with impairment of G2/M phase transition, cytokinesis defects and the onset of cell senescence. Mechanistically, we demonstrated a Sema4C/PlexinB2/LARG-dependent signaling cascade that is required to maintain critical RhoA-GTP levels in cancer cells. Interestingly, we also found that Sema4C upregulation in luminal-type breast cancer cells drives a dramatic phenotypic change, with disassembly of polarity complexes, mitotic spindle misorientation, cell-cell dissociation and increased migration and invasiveness. We found that this signaling cascade is dependent on the PlexinB2 effectors ErbB2 and RhoA-dependent kinases. Moreover, Sema4C-overexpressing luminal breast cancer cells upregulated the transcription factors Snail, Slug and SOX-2, and formed estrogen-independent metastatic tumors in mice. In sum, our data indicate that Sema4C/PlexinB2 signaling is essential for the growth of breast carcinoma cells, featuring a novel potential therapeutic target. In addition, elevated Sema4C expression enables indolent luminal-type tumors to become resistant to estrogen deprivation, invasive and metastatic in vivo, which could account for its association with a subset of human breast cancers with poor prognosis.

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Section: Sema4c/plexinb2/larg-dependent Rhoa Signaling Is Required Tosupporting

confidence: 73%

Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential

Gurrapu

Pupo

Franzolin³

et al. 2018

Cell Death Differ

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“…Other candidate interactors might be relevant to the functions of Rnd2 in adult-born DGNs. For example, semaphorin receptors, known as Plexins, have been implicated in AHN (Duan et al, 2014;Jongbloets et al, 2017;Mata et al, 2018;Zhao et al, 2018) and have been shown to be bound and regulated by Rnd2 in neurons and other cell types (Azzarelli et al, 2014;McColl et al, 2016;Uesugi et al, 2009). Nevertheless, whether Plexins mediate some aspects of Rnd2 action in adult newborn neurons remains unknown.…”

Section: Rnd2 Has Unique Functions In the Development Of Adult-born Dgnsmentioning

confidence: 99%

The atypical Rho GTPase Rnd2 is critical for dentate granule neuron development and anxiety-like behavior during adult but not neonatal neurogenesis

Kerloch

Farrugia

Maître

et al. 2020

Preprint

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Despite the central role of Rho GTPases in neuronal development, their functions in adult hippocampal neurogenesis remain poorly explored. Here, by using a retrovirus-based loss-of-function approach in vivo, we show that the atypical Rho GTPase Rnd2 is crucial for the survival, positioning, somatodendritic morphogenesis and functional maturation of adult-born dentate granule neurons. Interestingly, most of these functions are specific to granule neurons generated during adulthood since the deletion of Rnd2 in neonatally-born granule neurons only affects dendritogenesis. In addition, suppression of Rnd2 in adult-born dentate granule neurons increases anxiety-like behaviour whereas its deletion in pups has no such effect, a finding supporting the adult neurogenesis hypothesis of anxiety disorders. Thus, our results provide mechanistic insight into the differential regulation of hippocampal neurogenesis during development and adulthood, and establishes a causal relationship between Rnd2 expression and anxiety.

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“…Plexin stimulation delivers directional cues for cell migration and axon guidance through the regulation of several small GTPases and semaphorin-plexin signalling can either be attractive or repulsive depending on the particular plexin co-receptor expressed (4,5), while nonpolarised stimulation of cells with semaphorins results in cell collapse (6). B-class plexins can interact with the GTPases Rnd1-3 (7,8), Rac (9), RhoD(10), R-Ras (7) and M-Ras (11) and regulate Rho via PDZRhoGEF/LARG (12) and p190RhoGAP (13). In addition, the plexin cytoplasmic tail contains a GTPase activating protein (GAP) domain (14) divided into two regions by a Rho Binding domain (RBD) (15) and plexins act as GAPs for Rap1B and Rap2A (16).…”

Section: Introductionmentioning

confidence: 99%

Plexin-B1 mutation drives prostate cancer metastasis

Shorning

Trent

Griffiths

et al. 2020

Preprint

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Prostate cancer mortality is associated with the metastatic spread of tumour cells. A better understanding of the mechanisms which allow a locally advanced tumour to disseminate around the body will identify new therapeutic targets to block this process. One of set of genes implicated in metastasis are plexins, which can promote or suppress tumour progression depending on cancer type and cellular context. We have taken a mouse genetics approach to gain insight into the role of Plexin-B1 in prostate cancer progression in vivo.We show here that genetic deletion of Plexin-B1 in PbCre+Ptenfl/flKrasG12V and PbCre+Ptenfl/flp53fl/fl mouse prostate cancer models significantly decreased metastasis. High levels of prostate epithelial cell-specific expression of wild-type Plexin-B1 in knock-in mice with a PbCre+Ptenfl/flKrasG12V background also significantly decreased metastasis. In contrast, expression of a Plexin-B1 mutant (P1597L; identified from metastatic deposits in prostate cancer patients) in prostate epithelial cells in PbCre+Ptenfl/flKrasG12V and PbCre+Ptenfl/flp53fl/fl mice significantly increased metastasis, in particular metastasis to distant sites. In line with these findings, both deletion and overexpression of wild-type Plexin-B1 reduced invasion of tumour cells into the prostate stroma, while overexpression of mutant Plexin-B1 significantly increased invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Invasion and metastasis also correlated with phosphorylation of myosin light chain, suggesting that Plexin-B1 signals via the Rho/ROCK pathway to promote metastasis.Our results demonstrate that mutant Plexin-B1 promotes metastasis in prostate cancer and represents a new therapeutic target to suppress tumour spread.

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Rnd3-induced cell rounding requires interaction with Plexin-B2

Cited by 21 publications

References 52 publications

Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential

Sema4C/PlexinB2 signaling controls breast cancer cell growth, hormonal dependence and tumorigenic potential

The atypical Rho GTPase Rnd2 is critical for dentate granule neuron development and anxiety-like behavior during adult but not neonatal neurogenesis

Plexin-B1 mutation drives prostate cancer metastasis

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