The WNT/β-catenin signaling pathway controls stem and progenitor cell proliferation, survival and differentiation in epithelial tissues. Aberrant stimulation of this pathway is therefore frequently observed in cancers from epithelial origin. For instance, colorectal and hepatic cancers display activating mutations in the CTNNB1 gene encoding β-catenin, or inactivating APC and AXIN gene mutations. However, these mutations are uncommon in breast and pancreatic cancers despite nuclear β-catenin localization, indicative of pathway activation. Notably, the low-density lipoprotein receptor-related protein 6 (LRP6), an indispensable co-receptor for WNT, is frequently overexpressed in colorectal, liver, breast and pancreatic adenocarcinomas in association with increased WNT/β -catenin signaling. Moreover, LRP6 is hyperphosphorylated in KRAS-mutated cells and in patient-derived colorectal tumours. Polymorphisms in the LRP6 gene are also associated with different susceptibility to developing specific types of lung, bladder and colorectal cancers. Additionally, recent observations suggest that LRP6 dysfunction may be involved in carcinogenesis. Indeed, reducing LRP6 expression and/or activity inhibits cancer cell proliferation and delays tumour growth in vivo. This review summarizes current knowledge regarding the biological function and regulation of LRP6 in the development of epithelial cancers—especially colorectal, liver, breast and pancreatic cancers.
Over the past 2 decades, pattern recognition receptors (PRRs) have been shown to be on the front line of many illnesses such as autoimmune, inflammatory, and neurodegenerative diseases as well as allergies and cancer. Among PRRs, toll-like receptors (TLRs) are the most studied family. Dissecting TLRs signaling turned out to be advantageous to elaborate efficient treatments to cure autoimmune and chronic inflammatory disorders. However, a broad understanding of TLR effectors is required to propose a better range of cures. In addition to kinases and E3 ubiquitin ligases, phosphatases emerge as important regulators of TLRs signaling mediated by NF-κB, type I interferons (IFN I) and Mitogen-Activated Protein Kinases signaling pathways. Here, we review recent knowledge on TLRs signaling modulation by different classes and subclasses of phosphatases. Thus, it becomes more and more evident that phosphatases could represent novel therapeutic targets to control pathogenic TLRs signaling. Graphic abstract
Toll-like receptors (TLRs) are the most studied receptors among the pattern recognition receptors (PRRs). They act as microbial sensors, playing major roles in the regulation of the innate immune system. TLRs mediate their cellular functions through the activation of MyD88-dependent or MyD88-independent signaling pathways. Myd88, or myeloid differentiation primary response 88, is a cytosolic adaptor protein essential for the induction of proinflammatory cytokines by all TLRs except TLR3. While the crucial role of Myd88 is well described, the contribution of other adaptors in mediating TLR signaling and function has been underestimated. In this review, we highlight important results demonstrating that TIRAP and TRAM adaptors are also required for full signaling activity and responses induced by most TLRs.
Intestinal epithelial self-renewal is tightly regulated by signaling pathways controlling stem cell proliferation, determination and differentiation. In particular, Wnt/β-catenin signaling controls intestinal crypt cell division, survival and maintenance of the stem cell niche. Most colorectal cancers are initiated by mutations activating the Wnt/β-catenin pathway. Wnt signals are transduced through Frizzled receptors and LRP5/LRP6 coreceptors to downregulate GSK3β activity, resulting in increased nuclear β-catenin. Herein, we explored if LRP6 expression is required for maintenance of intestinal homeostasis, regeneration and oncogenesis. Mice with an intestinal epithelial cell-specific deletion of Lrp6 (Lrp6IEC-KO) were generated and their phenotype analyzed. No difference in intestinal architecture nor in proliferative and stem cell numbers was found in Lrp6IEC-KO mice in comparison to controls. Nevertheless, using ex vivo intestinal organoid cultures, we found that LRP6 expression was critical for crypt cell proliferation and stem cell maintenance. When exposed to dextran sodium sulfate, Lrp6IEC-KO mice developed more severe colitis than control mice. However, loss of LRP6 did not affect tumorigenesis in ApcMin/+ mice nor growth of human colorectal cancer cells. By contrast, Lrp6 silencing diminished anchorage-independent growth of BRafV600E-transformed intestinal epithelial cells (IEC). Thus, LRP6 controls intestinal stem cell functionality and is necessary for BRAF-induced IEC oncogenesis.
Intestinal epithelial self-renewal is tightly regulated by signaling pathways controlling stem cell proliferation, determination and differentiation. In particular, Wnt/β-catenin signaling controls crypt cell division and survival and is required for maintenance of the intestinal stem cell niche. Most colorectal cancers are also initiated by mutations activating the Wnt/β-catenin pathway. Wnt signals are transduced through Frizzled receptors and LRP5/LRP6 coreceptors to downregulate GSK3β activity, resulting in increased nuclear β-catenin. Herein, we explored if LRP6 expression is required for maintenance of intestinal homeostasis, regeneration and oncogenesis. Mice with an intestinal epithelial cell-specific deletion of Lrp6 (Lrp6IEC-KO) were generated and their phenotype analyzed. No difference in intestinal architecture or in proliferative and stem cell numbers was found in Lrp6IEC-KO mice in comparison to controls. Nevertheless, using ex vivo intestinal organoid cultures, we found that LRP6 expression was critical for crypt cell proliferation and stem cell maintenance. When exposed to dextran sodium sulfate, Lrp6IEC-KO mice developed more severe colitis than control mice. However, loss of LRP6 did not affect tumorigenesis in Apc Min/+ mice nor growth of human colorectal cancer cells. By contrast, Lrp6 silencing diminished anchorage-independent growth of BRafV600E-transformed IEC. Thus, LRP6 controls intestinal stem cell functionality and is necessary for BRAF-induced IEC oncogenesis.
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