さらにニューヨークのMasagueさんの所からはnature medicineに乳癌をモデルにtenascin C (TNC)とWntシグナル特にLgr5の関係についての報告が出ておりその論文の関連遺伝子は下記↓の通りである。
- musashi homolog 1 (MSI1)
- leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5).
- nanog homeobox (NANOG),
- POU class 5 homeobox 1 (POU5F1), also known as OCT4
- SRY-box 2 (SOX2).
まずはPNASから
Proc Natl Acad Sci U S A.2011 Jun 21
R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/β-catenin signaling
Biological Sciences - Cell Biology
Kendra S. Carmon, Xing Gong, Qiushi Lin, Anthony Thomas, and Qingyun Liu
The Wnt/β-catenin signaling system plays essential roles in embryonic development and in the self-renewal and maintenance of adult stem cells. R-spondins (RSPOs) are a group of secreted proteins that enhance Wnt/β-catenin signaling and have pleiotropic functions in development and stem cell growth. LGR5, an orphan receptor of the G protein-coupled receptor (GPCR) superfamily, is specifically expressed in stem cells of the intestinal crypt and hair follicle. Knockout of LGR5 in the mouse results in neonatal lethality. LGR4, a receptor closely related to LGR5, also has essential roles in development, as its knockout leads to reduced viability and retarded growth. Overexpression of both receptors has been reported in several types of cancer. Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/β-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. Interestingly, neither receptor is coupled to heterotrimeric G proteins or to β-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. The findings provide a basis for stem cell-specific effects of Wnt/β-catenin signaling and for the broad range of functions LGR4, LGR5, and the R-spondins have in normal and malignant growth.
ーーーーーーーーーーーーーーーーーーーーーーーーーーーーーーーーー
続いてNature Medicine(2011)
Published online 26 June 2011
Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs
Thordur Oskarsson,Swarnali Acharyya,Xiang H-F Zhang, Sakari Vanharanta, Sohail F Tavazoie, Patrick G Morris, Robert J Downey, Katia Manova-Todorova, Edi Brogi & Joan Massagué
We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell-derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSI1-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell-derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche.
ーーーーーーーーーーーーーーーーーーーーーーーーーーーーーーーーー
最後にnature
Nature(2011)
Published online 04 July 2011
Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling
Wim de Lau, Nick Barker, Teck Y. Low, Bon-Kyoung Koo, Vivian S. W. Li, Hans Teunissen, Pekka Kujala, Andrea Haegebarth, Peter J. Peters, Marc van de Wetering, D. E. Stange, J. van Es, Daniele Guardavaccaro, Richard B. M. Schasfoort, Yasuaki Mohri, Katsuhiko Nishimori, Shabaz Mohammed, Albert J. R. Heck & Hans Clevers
The adult stem cell marker Lgr5 and its relative Lgr4 are often co-expressed in Wnt-driven proliferative compartments. We find that conditional deletion of both genes in the mouse gut impairs Wnt target gene expression and results in the rapid demise of intestinal crypts, thus phenocopying Wnt pathway inhibition. Mass spectrometry demonstrates that Lgr4 and Lgr5 associate with the Frizzled/Lrp Wnt receptor complex. Each of the four R-spondins, secreted Wnt pathway agonists, can bind to Lgr4, -5 and -6. In HEK293 cells, RSPO1 enhances canonical WNT signals initiated by WNT3A. Removal of LGR4 does not affect WNT3A signalling, but abrogates the RSPO1-mediated signal enhancement, a phenomenon rescued by re-expression of LGR4, -5 or -6. Genetic deletion of Lgr4/5 in mouse intestinal crypt cultures phenocopies withdrawal of Rspo1 and can be rescued by Wnt pathway activation. Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. These results will guide future studies towards the application of R-spondins for regenerative purposes of tissues expressing Lgr5 homologues.
0 件のコメント:
コメントを投稿