LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence

Ren, Qian; Chen, Jiongcheng; Liu, Youhua

doi:10.3389/fcell.2021.670960

Cited by 99 publications

(75 citation statements)

References 108 publications

(180 reference statements)

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“…In addition, the human Lrp6 crystal structure protein has been characterised using electron microscopy (EM) and other molecular/bioinformatic tools [ 10 , 11 , 12 , 13 , 14 , 15 ] ( Figure 2 B). LRP6-E1E2 or LRP6-E3E4 proteins were purified and concentrated for crystallisation [ 10 ].…”

Section: Lrp6 Structure and Homologymentioning

confidence: 99%

“…Moreover, embryos die shortly after gastrulation in Lrp5+/−; Lrp6−/− mutants [ 31 ]. This study suggested a functional redundancy between Lrp6 and Lrp5, but that Lrp6 plays a more essential role in development [ 11 ]. Importantly, total inactivation of Lrp6 led to multiple abnormalities in many organs, including the heart, eyes, limbs, brain, and developing spinal cord, and resulted in perinatal mortality [ 39 , 40 ].…”

Section: Lrp6 Expression and Function During Developmentmentioning

confidence: 99%

“…Further research is needed to develop specific inhibitor or activator drugs to target Lrp6. However, it is worth mentioning that some reports have suggested that LRP6 could interact with other pathways independently from Wnt/β-catenin and, in turn, regulate different biological functions [ 11 , 23 ]. For example, LRP6 could regulate the Wnt/PCP pathway and is implicated in cell polarity through RhoA activity [ 37 , 43 ].…”

Section: Lrp6 As a Potential Therapeutic Targetmentioning

confidence: 99%

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LRP6 Receptor Plays Essential Functions in Development and Human Diseases

Alrefaei

Abu‐Elmagd

2022

Genes

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LRP6 is a member of the low-density lipoprotein receptor superfamily of cell-surface receptors. It is required for the activation of the Wnt/β-catenin signalling pathway. LRP6 is detected in different tissue types and is involved in numerous biological activities such as cell proliferation, specification, metastatic cancer, and embryonic development. LRP6 is essential for the proper development of different organs in vertebrates, such as Xenopus laevis, chickens, and mice. In human, LRP6 overexpression and mutations have been reported in multiple complex diseases including hypertension, atherosclerosis, and cancers. Clinical studies have shown that LRP6 is involved in various kinds of cancer, such as bladder and breast cancer. Therefore, in this review, we focus on the structure of LRP6 and its interactions with Wnt inhibitors (DKK1, SOST). We also discuss the expression of LRP6 in different model systems, with emphasis on its function in development and human diseases.

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Section: Lrp6 Structure and Homologymentioning

confidence: 99%

Section: Lrp6 Expression and Function During Developmentmentioning

confidence: 99%

Section: Lrp6 As a Potential Therapeutic Targetmentioning

confidence: 99%

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LRP6 Receptor Plays Essential Functions in Development and Human Diseases

Alrefaei

Abu‐Elmagd

2022

Genes

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“…However, to our knowledge, the regulation of these receptors by GSIs have not been investigated specifically within skeletal muscle. Another γ-secretase substrate, low-density lipoprotein receptor-related protein 6 (LRP6), is a transmembrane receptor crucial to canonical Wnt signaling [62,63]. Crosstalk between Notch and Wnt have been widely discussed for proper skeletal muscle regeneration, while LRP6-mTOR signaling has been investigated in cardiomyocytes of 13 and hepatocytes [1,64,65].…”

Section: Discussionmentioning

confidence: 99%

GSI Treatment Preserves Protein Synthesis in C2C12 Myotubes

Huot

Thompson

McMullen

et al. 2021

Cells

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It has been demonstrated that inhibiting Notch signaling through γ-secretase inhibitor (GSI) treatment increases myogenesis, AKT/mTOR signaling, and muscle protein synthesis (MPS) in C2C12 myotubes. The purpose of this study was to determine if GSI-mediated effects on myogenesis and MPS are dependent on AKT/mTOR signaling. C2C12 cells were assessed for indices of myotube formation, anabolic signaling, and MPS following GSI treatment in combination with rapamycin and API-1, inhibitors of mTOR and AKT, respectively. GSI treatment increased several indices of myotube fusion and MPS in C2C12 myotubes. GSI-mediated effects on myotube formation and fusion were completely negated by treatment with rapamycin and API-1. Meanwhile, GSI treatment was able to rescue MPS in C2C12 myotubes exposed to rapamycin or rapamycin combined with API-1. Examination of protein expression revealed that GSI treatment was able to rescue pGSK3β Ser9 despite AKT inhibition by API-1. These findings demonstrate that GSI treatment is able to rescue MPS independent of AKT/mTOR signaling, possibly via GSK3β modulation.

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“…These changes go hand in hand with the inactivation of canonical Wnt signaling and activation of non-canonical Wnt signaling pathways (MacDonald et al, 2009;Ren et al, 2021). Furthermore, there was a synergistic effect of non-canonical Wnt5a and Wnt11 in ASMCs to induce cardiac differentiation by increasing the expression cardiac markers.…”

Section: Non-canonical Wnt Ligands Wnt5a and Wnt11 Induces Cardiogenesis And Maintains Viability After Hypoxic Injurymentioning

confidence: 99%

Amniotic stromal stem cell‐loaded hydrogel repairs cardiac tissue in infarcted rat hearts via paracrine mediators

Khan

Makhoul

et al. 2021

J Tissue Eng Regen Med

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The use of stem cells to repair the heart after a myocardial infarction (MI) remains promising, yet clinical trials over the past 20 years suggest that cells fail to integrate into the native tissue, resulting in limited improvements in cardiac function. Here, we demonstrate the cardioprotective potential of a composite inserting human amniotic stromal mesenchymal stem cells (ASMCs) in a chitosan and hyaluronic acid (C/HA) based hydrogel in a rat MI model. Mechanical characterization of the C/HA platform indicated a swift elastic conversion at 40°C and a rapid sol-gel transition time at 37°C. Cell viability assay presented active and proliferating AMSCs in the C/ HA. The ASMCs + C/HA injected composite significantly increased left ventricular ejection fraction, fractional shortening, and neovessel formation. The encapsulated AMSCs were abundantly detected in the infarcted myocardium 6 weeks postadministration and co-expressed cardiac proteins and notably proliferative markers. Proteomic profiling revealed that extracellular vesicles released from hypoxia preconditioned ASMCs contained proteins involved in cytoprotection, angiogenesis, cardiac differentiation and non-canonical Wnt-signaling. Independent activation of non-canonical Wnt-signaling pathways in ASMCs induced cardiogenesis. Despite a low injected cellular density at baseline, the encapsulated AMSCs were abundantly retained and increased cardiac function. Furthermore, the C/HA hydrogel provided an active milieu for the AMSCs to proliferate, co-express cardiac proteins, and induce new vessel formation. Hence, this novel composite of AMSCs + C/HA scaffold is a conceivable candidate that could restore cardiac function and reduce remodeling.

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LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence

Cited by 99 publications

References 108 publications

LRP6 Receptor Plays Essential Functions in Development and Human Diseases

LRP6 Receptor Plays Essential Functions in Development and Human Diseases

GSI Treatment Preserves Protein Synthesis in C2C12 Myotubes

Amniotic stromal stem cell‐loaded hydrogel repairs cardiac tissue in infarcted rat hearts via paracrine mediators

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