Overexpression of CD109 in the Epidermis Differentially Regulates ALK1 Versus ALK5 Signaling and Modulates Extracellular Matrix Synthesis in the Skin

Abstract

Transforming growth factor-β (TGF-β) is a multifunctional growth factor involved in many physiological processes including wound healing and inflammation. Excessive TGF-β signaling in the skin has been implicated in fibrotic skin disorders such as keloids and scleroderma. We previously identified CD109 as a TGF-β co-receptor and inhibitor of TGF-β signaling and have shown that transgenic mice overexpressing CD109 in the epidermis display decreased scarring. In certain cell types, in addition to the canonical type I receptor, ALK5, which activates Smad2/3, TGF-β can signal through another type I receptor, ALK1, which activates Smad1/5. Here we demonstrate that ALK1 is expressed and co-localizes with CD109 in mouse keratinocytes and that mice overexpressing CD109 in the epidermis display enhanced ALK1-Smad1/5 signaling but decreased ALK5-Smad2/3 signaling, TGF-β expression, and extracellular matrix production in the skin when compared with wild-type littermates. Furthermore, treatment with conditioned media from isolated keratinocytes or epidermal explants from CD109 transgenic mouse skin leads to a decrease in extracellular matrix production in mouse skin fibroblasts. Taken together, our findings suggest that CD109 differentially regulates TGF-β-induced ALK1-Smad1/5 versus ALK5-Smad2/3 pathways, leading to decreased extracellular matrix production in the skin and that epidermal CD109 expression regulates dermal function through a paracrine mechanism.

Encapsulation and Delivery of Neutrophic Proteins and Hydrophobic Agents Using PMOXA–PDMS–PMOXA Triblock Polymersomes

“… 44 − 47 CD109 is a membrane protein, approximately 180 kDa, which binds to TGF-β and represses TGF-β signaling in human keratinocytes. 48 − 51 Because curcumin and proteins such as CD109, NGF, and BDNF are unstable in biological environments, 52 , 53 it is advantageous to incorporate them into nanocarriers to protect them from hydrolytic and enzymatic cleavage to reach the site of injury.…”

FAD104, a regulator of adipogenesis, is a novel suppressor of TGF-β–mediated EMT in cervical cancer cells

“…Recently, Vorstenbosch et al . reported that CD109, a glycosylphosphatidylinositol (GPI)-anchored protein, directly interacts with ALK5 and ALK1 and inhibits Smad2/3 activation while enhancing Smad1/5 activation in keratinocytes 41 . On the other hand, it was reported that reduced levels of expression of Bmal1, an essential clock transcription activator, increased TGF-β–mediated phosphorylation levels of Smad1/5/8 but decreased phosphorylation levels of Smad2/3 in primary human articular chondrocytes and C3H10T1/2 cells 42 , 43 .…”

CD109: a multifunctional GPI‐anchored protein with key roles in tumor progression and physiological homeostasis

“…Their results suggested that K14‐CD109 transgenic mice were resistant to bleomycin‐induced skin fibrosis and showed reduced dermal thickness and decreased fibrotic response in wounds as compared with WT mice. Interestingly, these results were accompanied by increases in STAT3 signaling in CD109‐deficient mice and decreases in TGF‐β signaling in K14‐CD109 transgenic mice …”

“…CD109 is a multifunctional coreceptor that promotes tumor initiation, progression, and metastasis Although CD109 function has been extensively studied, its detailed biological role remains unclear. The primary function of CD109 reportedly involves downregulating transforming growth factor (TGF)-β signaling through its binding to TGF-β receptor I [activin receptor-like kinase (ALK)5], 53 TGF-β, 54 ALK1, 55 and 78-kDa glucose-regulated protein (GRP78) 56 in vitro. Both GPI-anchored CD109 and soluble CD109 bind to TGF-β receptors and attenuate TGF-β-induced SMAD2/3 phosphorylation (Fig.…”

“…18 by increases in STAT3 signaling in CD109-deficient mice 8 and decreases in TGF-β signaling in K14-CD109 transgenic mice. 55 The roles of CD109 in tumors have also been examined in vivo. A previous study demonstrated that CD109 promotes the initiation of skin squamous cell tumors exhibiting suppressed TGF-β signaling, 51 the progression of gliomas with resistance to chemotherapy, 18 and metastasis of lung adenocarcinoma cells exhibiting enhanced STAT3 phosphorylation 19 in specific mouse models, respectively.…”