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E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo

ABSTRACT: E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo

PROVIDER: PRJNA474104 | ENA |

REPOSITORIES: ENA

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E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo

Project description:Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are connected in vivo is largely unknown. We herein report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin and the spindle positioning determinant LGN interacts with the PDZ domain of cell polarity protein SCRIB and form a ternary protein complex to bridge cell polarity and cell division orientation. These findings provide a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial integrity and to prevent carcinogenesis in vivo.

2018-08-01 | GSE115204 | GEO

Annexin A1 is a polarity cue that directs planar mitotic spindle orientation during mammalian epithelial morphogenesis

Project description:Oriented cell divisions are critical for the formation and maintenance of structured epithelia. Proper mitotic spindle orientation relies on polarised anchoring of force generators to the cell cortex by the evolutionarily conserved Gαi-LGN-NuMA complex. However, the polarity cues that control cortical patterning of this ternary complex remain largely unknown in mammalian epithelia. Here we identify the membrane-associated protein Annexin A1 (ANXA1) as a novel interactor of LGN in mammary epithelial cells. ANXA1 acts independently of Gαi to instruct the accumulation of LGN and NuMA at the lateral cortex to ensure cortical anchoring of Dynein-Dynactin and astral microtubules and thereby planar alignment of the mitotic spindle. Loss of ANXA1 randomises mitotic spindle orientation, which in turn disrupts epithelial architecture and lumen formation in three-dimensional (3D) primary mammary organoids. Our findings establish ANXA1 as an upstream cortical cue that regulates LGN to direct planar cell divisions during mammalian epithelial morphogenesis.

2022-12-02 | PXD027452 | Pride

E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo.

Project description: Not available

| S-EPMC6115016 | biostudies-literature

Centrosomal ALIX regulates mitotic spindle orientation by modulating astral microtubule dynamics

Project description:The orientation of the mitotic spindle (MS) is tightly regulated, but the molecular mechanisms are incompletely understood. Here we report a novel role for the multifunctional adaptor protein ALG-2-interacting protein X (ALIX) in regulating MS orientation in addition to its well-established role in cytokinesis. We show that ALIX is recruited to the pericentriolar material (PCM) of the centrosomes and promotes correct orientation of the MS in asymmetrically dividing Drosophila stem cells and epithelial cells, and symmetrically dividing Drosophila and human epithelial cells. ALIX-deprived cells display defective formation of astral microtubules (MTs), which results in abnormal MS orientation. Specifically, ALIX is recruited to the PCM via Drosophila Spindle defective 2 (DSpd-2)/Cep192, where ALIX promotes accumulation of g-tubulin and thus facilitates efficient nucleation of astral MTs. In addition, ALIX promotes MT stability by recruiting Microtubule Associated Protein 1S (MAP1S), which stabilizes newly formed MTs. Altogether, our results demonstrate a novel evolutionarily conserved role of ALIX in providing robustness to the orientation of the MS by promoting astral MT formation during asymmetric and symmetric cell division.

2018-06-04 | PXD009747 | Pride

Emx2 defines bidirectional polarity of neuromasts by changing hair-bundle orientation and not hair-cell positions

Project description:The bidirectional sensitivity of neuromasts to water flow in the zebrafish lateral line system is attributed to the opposite orientation of the hair bundles on top of sensory hair cells (HC) within a neuromast. After each HC precursor divides to form two nascent HCs, HCs of the same bundle orientation are positioned on one side of the neuromast, across from HCs with opposite bundle orientation. The transcription factor emx2 is expressed in only one of the sibling HCs. Loss or gain of function of emx2 in HCs causes unidirectional hair bundle orientation in neuromasts. It is not clear whether Emx2 is required specifically in establishing hair bundle orientation after HC formation or Emx2 has an earlier role in HC fate and/or positioning, which indirectly changes hair bundle orientation. A phenomenon, in which nascent sibling HCs exchange positions with each other, has been postulated to be the mechanism for HCs to acquire their designated positions within the neuromast. We asked whether Emx2 is involved in positional acquisition of HCs within the neuromast. Using live-imaging and our emx2 reporter we find that the HC rearrangement, redefined as two processes named Rock & Roll are required for HCs to acquire their positions. Although Emx2 regulates the duration of the Rock and the frequency of Roll of nascent HCs, it is not required for their positional acquisition. Instead, Emx2 regulates the morphology of nascent HCs, which facilitates the rearrangement process.

2021-01-19 | GSE152859 | GEO

FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning

Project description:The concerted action of many protein kinases helps orchestrate the error-free progression through mitosis of mammalian cells. The roles and regulation of some prominent mitotic kinases, such as cyclin-dependent kinases, are well-established. However, these and other known mitotic kinases alone cannot account for the extent of protein phosphorylation that has been reported during mammalian mitosis. Here we demonstrate that CK1α, of the casein kinase 1 family of protein kinases, localises to the spindle and is required for proper spindle-positioning and timely cell division. CK1α is recruited to the spindle by FAM83D, and cells devoid of FAM83D, or those harbouring CK1α-binding-deficient FAM83DF283A/F283A knockin mutation, display pronounced spindle-positioning defects, and a prolonged mitosis. Restoring FAM83D at the endogenous locus in FAM83D-/- cells, or artificially delivering CK1α to the spindle in FAM83DF283A/F283A cells, rescues these defects. These findings implicate CK1α as new mitotic kinase that orchestrates the kinetics and orientation of cell division.

2019-07-15 | PXD013808 | Pride

Cell polarity and spindle orientation in the distal epithelium of embryonic lung.

Project description: Not available

| S-EPMC3023987 | biostudies-literature

Discs large links spindle orientation to apical-basal polarity in Drosophila epithelia.

Project description: Not available

| S-EPMC3770898 | biostudies-literature

Connexin 43 maintains tissue polarity and regulates mitotic spindle orientation in the breast epithelium.

Project description: Not available

| S-EPMC6550011 | biostudies-literature

Kinetochore protein Cnn1 promotes sister chromatid bi-orientation by modulating intraKMN affinities in a biphasic, phospho-regulated manner.

Project description:Kinetochores are large proteinaceous structures that assemble on centromeres to align sister chromatids to the mitotic spindle and orchestrate their segregation to the daughter cells. At the core of kinetochores lies a network of proteins known as KMN, whose microtubule-binding activity is regulated by the Ipl1/Aurora B and Mps1 kinases. Here, we have characterized a novel structural yeast kinetochore protein named Cnn1 and show that it regulates KMN-spindle activity by modulating the affinity between the KMN subcomplexes at their basis. Cnn1 supports KMN from S phase to anaphase, and is controlled by the Cdc28, Mps1 and Ipl1 kinases. Cnn1 has evolved to associate the KMN complexes into a coherent network activity to ensure efficient

2012-05-06 | GSE31567 | GEO

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