The anti-tumor NC1 domain of collagen XIX inhibits the FAK/ PI3K/Akt/mTOR signaling pathway through αvβ3 integrin interaction

Oudart, Jean‐Baptiste; Doué, Manon; Vautrin, Alexia; Brassart, Bertrand; Sellier, Christèle; Dupont-Deshorgue, Aurélie; Monboisse, Jean-Claude; Maquart, François‐Xavier; Brassart‐Pasco, Sylvie; Ramont, Laurent

doi:10.18632/oncotarget.6399

Cited by 46 publications

(33 citation statements)

References 61 publications

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“…8, A-D). These results are not entirely surprising given a recent article showing that NC1 signals through RGD-dependent integrins in cancer cells (Oudart et al, 2016). Further support for this notion stems from the discoveries that a variety of RGD-dependent integrins are present in cortical and synaptosome extracts and that Parv + cells express β 1 (but not β 3 ) integrins (Fig.…”

Section: Mechanisms Underlying the Synaptogenic Function Of The Nc1 Dmentioning

confidence: 69%

Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex

Su¹,

Jiang²,

Lippold³

et al. 2016

J Exp Med

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Section: Mechanisms Underlying the Synaptogenic Function Of The Nc1 Dmentioning

confidence: 69%

Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex

Su¹,

Jiang²,

Lippold³

et al. 2016

J Exp Med

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“…It is likely that NC1-peptide serves as a ligand that exerts its effects in the seminiferous through integrin-based receptors in Sertoli cells, possibility involving signaling proteins FAK and Akt downstream based on studies in other epithelia. [60][61][62] Also, NC1-peptide likely exerts its effects though an "outside-in," but also an "inside-out," integrin-based signaling mechanism 63,64 since the use of its recombinant protein in Sertoli cells cultured in vitro, 14 or through its overexpression in Sertoli cells and with or without the presence of a signal peptide engineered into the 5′-end of the NC1 clone, 15 were found to be equally active to perturb Sertoli cell TJpermeability barrier function through changes in the distribution BTB-associated proteins at the cell-cell interface. In this context, it is of interest to note that the observations that NC1-peptide is a biologically active regulator are also supported by finding in other epithelia.…”

Section: Discussionmentioning

confidence: 99%

NC1‐peptide regulates spermatogenesis through changes in cytoskeletal organization mediated by EB1

Liu

et al. 2020

FASEB j.

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are contributed equally to the completion of this work.Abbreviations: +TIP, microtubule plus (+)-end tracking protein; AJ, adherens junction; aPKC, atypical protein kinase C; Arp3, actin-related protein 3; BM, basement membrane; BTB, blood-testis barrier; Crb3, Crumbs homolog-3; DAPI, 4', 6-diamidino-2-phenylindole; Dia1, Diaphanous-related formin-1; Dlg1, Discs large 1; Dvl3, Disheveled 3; EB1, end-binding protein 1; Eps8, epidermal growth factor receptor pathway substrate 8; ES, ectoplasmic specialization; Fzd3, Frizzled 3; F12/DMEM, Ham's F12 nutrient mixture/Dulbecco's modified Eagle's medium (1:1, vol/vol); GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GJ, gap junction; H&E, hematoxylin and eosin staining; IF, immunofluorescence microscopy; IgG, immunoglobulin; IP, immunoprecipitation; MAP1a, microtubule-associated protein 1a; MARK, microtubule affinity-regulatory kinase 4; MT, microtubule; mTOR, mammalian target of rapamycin; NC1 domain, non-collagenous domain 1; Pals1, protein associated with Lin-7 1; PatJ, Pals1-associated tight junction protein; Par6, partitioning-defective (Par) protein 6; rpS6, ribosomal protein S6; TJ, tight junction; ZO-1, zonula occludens-1. AbstractDuring the epithelial cycle of spermatogenesis, different sets of cellular events take place across the seminiferous epithelium in the testis. For instance, remodeling of the blood-testis barrier (BTB) that facilitates the transport of preleptotene spermatocytes across the immunological barrier and the release of sperms at spermiation take place at the opposite ends of the epithelium simultaneously at stage VIII of the epithelial cycle. These cellular events are tightly coordinated via locally produced regulatory biomolecules. Studies have shown that collagen α3 (IV) chains, a major constituent component of the basement membrane, release the non-collagenous (NC) 1 domain, a 28-kDa peptide, designated NC1-peptide, from the C-terminal region, via the action of MMP-9 (matrix metalloproteinase 9). NC1-peptide was found to be capable of inducing BTB remodeling and spermatid release across the epithelium. As such, the NC1-peptide is an endogenously produced biologically active peptide which coordinates these cellular events across the epithelium in stage VIII tubules. Herein, we used an animal model, wherein NC1-peptide cloned into the pCI-neo mammalian expression vector was overexpressed in the testis, to better understanding the molecular mechanism by which NC1-peptide regulated spermatogenic function. It was shown that NC1-peptide induced considerable downregulation on a number of cell polarity and planar cell polarity (PCP) proteins, and studies have shown these polarity and PCP proteins modulate spermatid polarity and adhesion via their effects on microtubule (MT) and F-actin cytoskeletal organization across the epithelium. More important, NC1-peptide exerted its effects by downregulating the expression of microtubule (MT) plus-end tracking protein (+TIP) called EB1 (end-binding protein 1). We cloned the full-length EB1 cDNA for its ov...

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“…Time course of the decreased expression levels of phosphorylated AKT (P-AKT; both S473 and T308) in PI3K inhibitor treatment in ex vivo organ culture AKT (S473) and AKT (T308) are phosphorylated over different time courses depending on the different cell types and experimental conditions [33][34][35]. To provide more information as to how the time course of phosphorylation of AKT (both S473 and T308) affected SMG development in the PI3K/mTOR signalling pathways, we performed Western blotting analysis of the expression levels of P-AKT (both S473 and T308) in SMGs at 15, 30, 60 and 120 min of treatment with LY294002.…”

Section: Resultsmentioning

confidence: 99%

Role of the mTOR signalling pathway in salivary gland development

et al. 2019

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Development of the salivary gland is characterized by extensive branching morphogenesis. Although various molecules have been implicated in salivary gland development, the role of the mammalian target of rapamycin (mTOR) signalling pathway, including both mTOR complexes 1 and 2 (mTORC1 and 2), in salivary gland development is unknown. Here, we examined protein expression levels related to the mTOR signalling pathway using an ex vivo submandibular salivary gland (SMG) organ culture. We showed that branching buds in the salivary glands were substantially decreased and phosphorylation of mTORC1 signalling pathway related proteins (mTOR, p70 ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E‐binding protein 1) was inhibited by rapamycin (an mTOR inhibitor). In addition, AKT, which is an upstream protein kinase of mTORC1 and is downstream of mTORC2, is inhibited by LY294002 (a phosphatidylinositol 3‐kinase inhibitor), but not by rapamycin. Moreover, rapamycin‐treated ICR neonatal mice exhibited a reduction in both body weight and salivary glands compared with vehicle‐treated neonatal mice. The present data indicate that the mTOR signalling pathway, including both mTORC1 and mTORC2, plays a critical role in salivary gland development both in ex vivo SMG organ culture and ICR neonatal mice in vivo.

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The anti-tumor NC1 domain of collagen XIX inhibits the FAK/ PI3K/Akt/mTOR signaling pathway through αvβ3 integrin interaction

Cited by 46 publications

References 61 publications

Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex

Collagen-derived matricryptins promote inhibitory nerve terminal formation in the developing neocortex

NC1‐peptide regulates spermatogenesis through changes in cytoskeletal organization mediated by EB1

Role of the mTOR signalling pathway in salivary gland development

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