Cadherin-11 Regulates Cell Proliferation via the PDGFRβ-ERK1/2 Signaling Pathway in Human Mesenchymal Stem Cells

Passanha, Fiona R; Divinagracia, Madeleine L; LaPointe, Vanessa

doi:10.1093/stmcls/sxab019

Cited by 7 publications

(19 citation statements)

References 44 publications

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“…A detailed description of how hMSC proliferation is controlled by a multitude of cell surface receptors will provide new avenues for cell fate control and regenerative medicine therapies. The decrease in PDGFR-α activity and the increase in PDGFR-β activity agree with the experimental results (Madarampalli et al, 2019;Passanha et al, 2022). The proposed crosstalk protein, DUSP1, had decreased activity which resulted in increased ERK activity and decreased cyclin-D1 activity, which we interpreted as decreased proliferation.…”

Section: Discussionsupporting

confidence: 87%

“…Therefore, the tight regulation of ERK (inhibiting its activity) is necessary for cell proliferation. We suggest cadherin-11 and its downstream effector β-catenin play a part in the control over ERK inhibition, explaining why the cadherin-11 knockdown results in decreased hMSC proliferation (as shown experimentally by Passanha et al, 2022).…”

Section: Discussionmentioning

confidence: 56%

“…We mimic the cadherin-11 knockdown by setting the initial cell-cell contact to 0. This way cadherin-11 can never be present during the simulation, similar to an experimental 𝑐 = 0 knockdown of the protein (Passanha et al, 2022).…”

Section: Cadherin-11 Knockdownmentioning

confidence: 53%

“… Passanha et al, 2022. also reported that cadherin-11-knockdown hMSCs have more phosphorylated ERKpositive nuclei and show decreased proliferation.…”

mentioning

confidence: 87%

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Computational Evidence for Multi-Layer Crosstalk Between the Cadherin-11 and PDGFR Pathways

Karagöz

Passanha

Robeerst

et al. 2022

Preprint

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Various cell surface receptors play an important role in the differentiation and self-renewal of human mesenchymal stem cells (hMSCs). One example of such receptors are the cadherins, which maintain cell-cell adhesion and mechanically couple cells together. Recently, cadherin-11, which is a member of the type II classical cadherin family, has been shown to be involved in the fate commitment of hMSCs. Interestingly, cadherin-11 has no known intrinsic signaling activity and is thought to affect cell behavior via interactions with other cell surface receptors. Members of the platelet-derived growth factor receptor (PDGFR) family are hypothesized to be one of the interaction partners of cadherin-11. Experiments confirmed that PDGFR-α binding to extracellular cadherin-11 regions increases the PDGFR-α activity, whereas the interaction between PDGFR-β and cadherin-11 suppresses the activity of the growth factor receptor. Cadherin-11 knockdown experiments also decreased cell proliferation. These interactions between cadherin-11 and PDGFRs indicate a crosstalk between these receptors and their downstream signaling activities but the nature of this crosstalk is not entirely known. In this study, we used a computational model to represent the experimentally proven interactions between cadherin-11 and the two PDGFRs and we inspected whether the crosstalk also exists downstream of the signaling initiated by the two receptor families. The computational framework allowed us to monitor the relative activity levels of each protein in the network. We performed model simulations to mimic the conditions of previous cadherin-11 knockdown experiments and to predict the effect of crosstalk on cell proliferation. Overall, our predictions suggest the existence of another layer of crosstalk, namely between Beta-catenin (downstream to cadherin-11) and an ERK inhibitor protein (e.g., DUSP1), different than the crosstalk at the receptor level between cadherin-11 and PDGFR-α and PDGFR-β. By investigating the multi-level crosstalk between cadherin and PDGFRs computationally, this study contributes to an improved understanding of the effect of cell surface receptors on hMSCs proliferation.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 56%

Section: Cadherin-11 Knockdownmentioning

confidence: 53%

“… Passanha et al, 2022. also reported that cadherin-11-knockdown hMSCs have more phosphorylated ERKpositive nuclei and show decreased proliferation.…”

mentioning

confidence: 87%

See 2 more Smart Citations

Computational Evidence for Multi-Layer Crosstalk Between the Cadherin-11 and PDGFR Pathways

Karagöz

Passanha

Robeerst

et al. 2022

Preprint

Self Cite

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“…Increased regulation of FCGR2A in our data following treatment with asprosin ( Figure 2 ), may present a role in therapeutic response that requires future exploration. Furthermore, Cadherin 11 (CDH11), a membrane protein involved in calcium-dependant cell adhesion, essential for bone development and maintenance, is capable of regulating proliferation via ERK 1/2 signalling pathways [ 37 , 38 ]. In OvCa, CDH11 is connected to advanced stage and nodal involvement [ 39 ], in addition to migration and metastasis [ 37 ], yet displays limited involvement in cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Genes by the Glucogenic Hormone Asprosin in Ovarian Cancer

Kerslake

Sisu

Panfilov

et al. 2022

JCM

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Background: Ovarian cancer (OvCa) is one of the most lethal forms of gynaecological malignancy. Altered energy metabolism and increased aerobic glycolysis in OvCa are hallmarks that demand attention. The glucogenic hormone asprosin is often dysregulated in metabolic disorders such as insulin resistance, diabetes (type 2 and gestational), and preeclampsia. Despite association with metabolic disorders, its role in energy metabolism within the tumour microenvironment is yet to be explored. Here, we study the role of asprosin in OvCa using transcriptomics and expand on functional studies with clinical samples. Methods: RNA sequencing, functional gene enrichment analysis, Western blotting and ImageStream. Results: Following treatment with 100 nM of asprosin, the serous OvCa cell line, SKOV-3, displayed 160 and 173 gene regulatory changes, at 4 and 12 h respectively, when compared with control samples (p < 0.05 and Log2FC > 1). In addition to energy metabolism and glucose-related pathways, asprosin was shown to alter pathways associated with cell communication, TGF-β signalling, and cell proliferation. Moreover, asprosin was shown to induce phosphorylation of ERK1/2 in the same in vitro model. Using liquid biopsies, we also report for novel expression of asprosin’s predicted receptors OR4M1 and TLR4 in cancer-associated circulating cells; with significant reduction seen between pre-chemotherapy and end of first line chemotherapy, in addition to patients under maintenance with bevacizumab +/− olaparib for OR4M1. Conclusions: In relation to OvCa, asprosin appears to regulate numerous signalling pathways in-vitro. The prognostic potential of OR4M1 in liquid biopsies should also be explored further.

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Cdh11: Roles in different diseases and potential value in disease diagnosis and treatment

Zhang,

Wang,

Zhang

2023

Biochemistry and Biophysics Reports

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Cadherin-11 Regulates Cell Proliferation via the PDGFRβ-ERK1/2 Signaling Pathway in Human Mesenchymal Stem Cells

Cited by 7 publications

References 44 publications

Computational Evidence for Multi-Layer Crosstalk Between the Cadherin-11 and PDGFR Pathways

Computational Evidence for Multi-Layer Crosstalk Between the Cadherin-11 and PDGFR Pathways

Differential Regulation of Genes by the Glucogenic Hormone Asprosin in Ovarian Cancer

Cdh11: Roles in different diseases and potential value in disease diagnosis and treatment

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