Reactome | Regulation of CDH11 Expression and Function

Regulation of CDH11 Expression and Function

Stable Identifier

R-HSA-9759475

DOI

10.3180/R-HSA-9759475.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

Locations in the PathwayBrowser

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Cell-Cell communication (Homo sapiens)

- Cell junction organization (Homo sapiens)
  - Cell-cell junction organization (Homo sapiens)
    - Adherens junctions interactions (Homo sapiens)
      - Regulation of Homotypic Cell-Cell Adhesion (Homo sapiens)
        
        Regulation of Expression and Function of Type II Classical Cadherins (Homo sapiens)
        
        Regulation of CDH11 Expression and Function (Homo sapiens)

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Regulation of CDH11 Expression and Function

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CDH11 gene encodes Cadherin-11, also known as osteoblast cadherin (OB-cadherin). The CDH11 gene maps to chromosome 16, chromosomal band 16q22, which is a subject to recurrent genomic loss in some types of cancer. The CDH11 gene consists of 14 exons, which are known to encode two splicing isoforms. Both splicing isoforms are expressed in the heart, brain, placenta, lung and bone, but not in the kidney, skeletal muscle, pancreas and liver (Okazaki et al. 1994; Kawaguchi et al. 1999). Several transcription factors have been shown to directly regulate CDH11 gene transcription, including HOXC8 (Lei et al. 2005; Lei et al. 2006; Li et al. 2014), ILF3 (Zhang et al. 2017), ZEB2 (Nam et al. 2012; Nam et al. 2014), HEYL (Liu et al. 2020), FOXF1 (Black et al. 2018), and BHLHE22 (Ross et al. 2012), and the transcription of CDH11 has also been shown to be influenced by a number of growth factors and hormones, such as FGF2 (Strutz et al. 2002; James et al. 2008), TNF (Wu et al. 2013), TGFB1 (Schneider et al. 2012; Schulte et al. 2013; Hahn et al. 2016; Cheng et al. 2018; Ruan et al. 2019; Doolin et al. 2021; Wilson et al. 2022), TGFB2 (Wecker et al. 2013; Theodossiou et al. 2019), GNRH1 (Peng et al. 2015), PTH (Yao et al. 2014), dexamethasone (Lecanda et al. 2000), and progesterone (Chen et al. 1999). CDH11 can also affect TGFB1 signaling, thereby possibly creating a feedback loop (Passanha et al. 2022). Expression of mouse Cdh11 in mouse osteoblast-like cell line (MC3T3-E1) is not affected by osteogenic hormones triiodothyronine (T3) and 1,25-dihydroxyvitamin D3 at either mRNA or protein levels (Leugmayr et al. 2000). CDH11 mRNA has been identified as the target of several microRNAs, such as miR-200c-3p (Luo et al. 2013; Van der Goten et al. 2014) and miR-451a (Yamada et al. 2018; Wang et al. 2020; Wang et al. 2021).

Like other classical cadherins, CDH11 associates with several catenin proteins through its intracellular domain, which is thought to play a role in the establishment and regulation of adherens junctions: CTNND1 (also known as p120 catenin or delta-catenin), CTNNB1 (beta-catenin), JUP (Junction Plakoglobin, also known as gamma-catenin), and CTNNA1 (alpha-catenin) (Straub et al. 2003; Kiener et al. 2006; Ortiz et al. 2015; Lee et al. 2018).

CDH11, through its C-terminus, also forms a complex with angiomotin (AMOT) isoform p80 (AMOT-2), which is implicated in CDH11-mediated cell migration and tumor cell invasiveness (Levchenko et al. 2004; Jiang et al. 2006; Yi et al. 2011; Oritz et al. 2015; Lee et al. 2018).

Through its extracellular region, CDH11 binds to the C-terminal fragment of ANGPTL4 (Angiopoietin-like-4), commonly known as cANGPTL4, which is implicated in the regulation of wound healing. The variant isoform of CDH11 (CDH11v), an 85 kDa membrane-bound fragment produced as a consequence of alternative splicing (Kawaguchi et al. 1999), can compete with the canonical CDH11 for cANGPTL4 binding, leading to diminished CTNNB1 release (Teo et al. 2017).

During normal development, CDH11 is implicated as a regulator of stem cell fate decisions, especially in mesodermal cell lineages (reviewed in Alimperti and Andreadis 2015), being particularly important for skeleton formation (reviewed in Marie et al. 2014).

Besides cancer (reviewed in Blaschuk and Devemy 2009, Niit et al. 2015, Chen et al. 2021), CDH11 has been implicated in several other diseases, such as rheumatoid arthritis (reviewed in Chang et al. 2010, Dou et al. 2013, Sfikakis et al. 2017, Senolt et al. 2019, Nygaard and Firestein 2020), fibrosis (reviewed in Agarwal 2014), cardiovascular diseases (reviewed in Boda-Heggemann et al. 2009, Huynh 2017, Du et al. 2021), and neuropsychiatric disorders (reviewed in Redies et al. 2012).

Literature References

PubMed ID	Title	Journal	Year
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10933223	The organization of adherens junctions in mouse osteoblast-like cells (MC3T3-E1) and their modulation by triiodothyronine and 1,25-dihydroxyvitamin D3 Glantschnig, H, Klaushofer, K, Varga, F, Luegmayr, E	Histochem Cell Biol	2000
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35416252	Cadherin-11 influences differentiation in human mesenchymal stem cells by regulating the extracellular matrix via the TGFβ1 pathway Passanha, FR, Geuens, T, LaPointe, VLS	Stem Cells	2022
25794160	AP-1 Transcription Factors c-FOS and c-JUN Mediate GnRH-Induced Cadherin-11 Expression and Trophoblast Cell Invasion Leung, PC, Wang, YL, Ma, L, Zhu, H, Peng, B, Klausen, C	Endocrinology	2015
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35197532	Integrated bioinformatics analysis identifies established and novel TGFβ1-regulated genes modulated by anti-fibrotic drugs McDonald, MN, Mobley, JA, Ashish, S, Neptune, ER, Chanda, D, Kumar, PL, Wilson, AC, Thannickal, VJ, Chiles, J	Sci Rep	2022
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25466890	Angiomotin is a novel component of cadherin-11/β-catenin/p120 complex and is critical for cadherin-11-mediated cell migration Liu, HC, Lin, SH, Bilen, MA, Yu, G, Lee, YC, Cho, H, Lin, SC, Yu-Lee, LY, Ortiz, A	FASEB J	2015
28660896	Valvular disease: Cadherin 11 in calcific aortic valve disease Huynh, K	Nat Rev Cardiol	2017
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29269046	TGF-β1 up-regulates cadherin-11 expression through Snail: A potential mechanism for human trophoblast cell differentiation Yi, Y, Leung, PCK, Cheng, JC, Chang, HM	Cell Signal	2018
10320525	Expression and function of the splice variant of the human cadherin-11 gene in subordination to intact cadherin-11 Machinami, R, Takeshita, S, Kawaguchi, J, Kashima, T, Imai, T, Kudo, A	J Bone Miner Res	1999
30538046	TGFβ2-induced tenogenesis impacts cadherin and connexin cell-cell junction proteins in mesenchymal stem cells Tokle, J, Schiele, NR, Theodossiou, SK	Biochem Biophys Res Commun	2019
27574697	Partial epithelial-mesenchymal transition in keloid scars: regulation of keloid keratinocyte gene expression by transforming growth factor-β1 Combs, KA, Supp, DM, McFarland, KL, Hahn, JM	Burns Trauma	2016
25771201	CDH2 and CDH11 act as regulators of stem cell fate decisions Andreadis, ST, Alimperti, S	Stem Cell Res	2015
30509494	CDH11 promotes liver fibrosis via activation of hepatic stellate cells Nie, Y, Wu, Y, Pan, R, Ruan, W, Shen, X	Biochem Biophys Res Commun	2019
24130169	ZEB2-Sp1 cooperation induces invasion by upregulating cadherin-11 and integrin α5 expression Nam, EH, Kim, S, Park, YK, Zhao, XF, Lee, Y, Lee, JW	Carcinogenesis	2014
23916685	Pressure and inflammatory stimulation induced increase of cadherin-11 is mediated by PI3K/Akt pathway in synovial fibroblasts from temporomandibular joint Gu, Z, Zhou, Y, Lu, H, Xu, T, Wu, M	Osteoarthritis Cartilage	2013
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34731044	Fibroblast to myofibroblast transition is enhanced by increased cell density Doolin, MT, Smith, IM, Stroka, KM	Mol Biol Cell	2021
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22284184	Bhlhb5 and Prdm8 form a repressor complex involved in neuronal circuit assembly Greenberg, ME, Harrar, D, McInnes, RR, Ross, SE, Lin, Y, Hemberg, M, Mok, SI, Salogiannis, J, Atan, D, Kim, TK, Hu, L, McCord, AE, Jung, C, Cohen, S	Neuron	2012
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