FGF18 alleviates sepsis-induced acute lung injury by inhibiting the NF-κB pathway.

BACKGROUND: Acute lung injury (ALI) is a devastating clinical disorder with a high mortality rate, and there is an urgent need for more effective therapies. Fibroblast growth factor 18 (FGF18) has potent anti-inflammatory properties and therefore has become a focus of research for the treatment of lung injury. However, the precise role of FGF18 in the pathological process of ALI and the underlying mechanisms have not been fully elucidated. METHODS: A mouse model of ALI and human umbilical vein endothelial cells (HUVEC) stimulated with lipopolysaccharide (LPS) was established in vivo and in vitro. AAV-FGF18 and FGF18 proteins were used in C57BL/6J mice and HUVEC, respectively. Vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and p65 protein levels were determined by western blotting or immunofluorescent staining. Afterward, related inhibitors were used to explore the potential mechanism by which FGF18 relieves inflammation. RESULTS: In this study, we found that FGF18 was significantly upregulated in LPS-induced ALI mouse lung tissues and LPS-stimulated HUVECs. Furthermore, our studies demonstrated that overexpressing FGF18 in the lung or HUVEC could significantly alleviate LPS-induced lung injury and inhibit vascular leakage. CONCLUSIONS: Mechanically, FGF18 treatment dramatically inhibited the NF-κB signaling pathway both in vivo and in vitro. In conclusion, these results indicate that FGF18 attenuates lung injury, at least partially, via the NF-κB signaling pathway and therefore may be a potential therapeutic target for ALI.

α-Catenin promotes dermal fibroblasts proliferation and migration during wound healing via FAK/YAP activation.

Skin wound healing is a complex and organized biological process, and the dermal fibroblasts play a crucial role. α-Catenin is known to be involved in regulating various cellular signals, and its role in wound healing remains unclear. Here, we have identified the pivotal role of the α-catenin/FAK/YAP signaling axis in the proliferation and migration of dermal fibroblasts, which contributes to the process of skin wound healing. Briefly, when α-catenin was knocked down specifically in dermal fibroblasts, the wound healing rate is significantly delayed. Moreover, interfering with α-catenin can impede the proliferation and migration of dermal fibroblasts both in vitro and in vivo. Mechanistically, the overexpression of α-catenin upregulates the nuclear accumulation of YAP and transcription of downstream target genes, resulting in enhanced the proliferation and migration of dermal fibroblasts. Furthermore, the FAK Tyr397 phosphorylation inhibitor blocked the promoting effects of α-catenin on YAP activation. Importantly, the continuous phosphorylation mutation of FAK Tyr397 reversed the retardatory effects of α-catenin knockdown on wound healing, by increasing the vitality of fibroblasts. Likewise, α-catenin/FAK was validated as a therapeutic target for wound healing in the db/db chronic trauma model. In summary, our findings have revealed a novel mechanism by which α-catenin facilitates the function of fibroblasts through the activity of the FAK/YAP signaling axis. These findings define a promising therapeutic strategy for accelerating the wound healing process.

FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice.

Hepatic ischemia-reperfusion injury (IRI) is a common complication occurs during hepatic resection and transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Here, we aim to explore the role of fibroblast growth factor 18 (FGF18) in hepatic IRI. In this work, we find that Hepatic stellate cells (HSCs) secrete FGF18 and alleviates hepatocytes injury. HSCs-specific FGF18 deletion largely aggravates hepatic IRI. Mechanistically, FGF18 treatment reduces the levels of ubiquitin carboxyl-terminal hydrolase 16 (USP16), leading to increased ubiquitination levels of Kelch Like ECH Associated Protein 1 (KEAP1) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, USP16 interacts and deubiquitinates KEAP1. More importantly, Nrf2 directly binds to the promoter of USP16 and forms a negative feedback loop with USP16. Collectively, our results show FGF18 alleviates hepatic IRI by USP16/KEAP1/Nrf2 signaling pathway in male mice, suggesting that FGF18 represents a promising therapeutic approach for hepatic IRI.

Erratum: FGF13 Is a Novel Regulator of NF-κB and Potentiates Pathological Cardiac Hypertrophy.

[This corrects the article DOI: 10.1016/j.isci.2020.101627.].

Fibroblast growth factor 18 alleviates stress-induced pathological cardiac hypertrophy in male mice.

Fibroblast growth factor-18 (FGF18) has diverse organ development and damage repair roles. However, its role in cardiac homeostasis following hypertrophic stimulation remains unknown. Here we investigate the regulation and function of the FGF18 in pressure overload (PO)-induced pathological cardiac hypertrophy. FGF18 heterozygous (Fgf18+/-) and inducible cardiomyocyte-specific FGF18 knockout (Fgf18-CKO) male mice exposed to transverse aortic constriction (TAC) demonstrate exacerbated pathological cardiac hypertrophy with increased oxidative stress, cardiomyocyte death, fibrosis, and dysfunction. In contrast, cardiac-specific overexpression of FGF18 alleviates hypertrophy, decreased oxidative stress, attenuates cardiomyocyte apoptosis, and ameliorates fibrosis and cardiac function. Tyrosine-protein kinase FYN (FYN), the downstream factor of FGF18, was identified by bioinformatics analysis, LC-MS/MS and experiment validation. Mechanistic studies indicate that FGF18/FGFR3 promote FYN activity and expression and negatively regulate NADPH oxidase 4 (NOX4), thereby inhibiting reactive oxygen species (ROS) generation and alleviating pathological cardiac hypertrophy. This study uncovered the previously unknown cardioprotective effect of FGF18 mediated by the maintenance of redox homeostasis through the FYN/NOX4 signaling axis in male mice, suggesting a promising therapeutic target for the treatment of cardiac hypertrophy.

FGF4 Promotes Skin Wound Repair through p38 MAPK and GSK3ß-Mediated Stabilization of Slug.

Cutaneous wound healing is an orderly and intricate process that restores the barrier function and integrity of injured skin. Re-epithelialization, which involves the proliferation and migration of keratinocytes to cover the denuded surface, is essential for successful wound closure. There are many members of the FGF family, of which the paracrine-acting FGF1 and FGF7 subfamily members have been identified as positive regulators of wound repair. However, the role and underlying mechanisms of some other paracrine FGFs in wound repair still remain obscure. In this report, we found that paracrine FGF4 localized predominantly to the epidermal keratinocytes and was markedly upregulated at the wound edges in response to re-epithelialization in human and mouse wound models. Blockade of FGF4 resulted in delayed re-epithelialization of human ex vivo skin wounds, whereas recombinant FGF4 treatment promoted re-epithelialization and wound repair. Mechanistically, recombinant FGF4 promotes p38 MAPK‒GSK3ß‒mediated stabilization of Slug by reducing its ubiquitination, which triggers epithelial-to-mesenchymal transition and promotes the migration and proliferation of keratinocytes and thus wound re-epithelialization. Our findings uncover FGF4 as an important regulator of wound healing, highlighting a promising therapeutic avenue for skin injury.

FGF13-Sensitive Alteration of Parkin Safeguards Mitochondrial Homeostasis in Endothelium of Diabetic Nephropathy.

Studies of diabetic glomerular injury have raised the possibility of developing useful early biomarkers and therapeutic approaches for the treatment of type 2 diabetic nephropathy (T2DN). In this study, we found that FGF13 expression is induced in glomerular endothelial cells (GECs) during T2DN progression. Endothelial-specific deletion of Fgf13 potentially alleviates T2DN damage, while Fgf13 overexpression has the opposite effect. Mechanistically, Fgf13 deficiency results in improved mitochondrial homeostasis and endothelial barrier integrity in T2DN. Moreover, FGF13-sensitive alteration of Parkin safeguards mitochondrial homeostasis in endothelium of T2DN through promotion of mitophagy and inhibition of apoptosis. Additionally, it is confirmed that the beneficial effects of Fgf13 deficiency on T2DN are abolished by endothelial-specific double deletion of Fgf13 and Prkn. The effects of Fgf13 deficiency on mitophagy and apoptosis through Parkin-dependent regulation may be distinct and separable events under diabetic conditions. These data show that the bifunctional role of Fgf13 deficiency in promoting mitophagy and inhibiting apoptosis through Parkin can shape mitochondrial homeostasis regulation in GECs and T2DN progression. As a potential therapeutic target for prevention and control of T2DN, a mechanistic understanding of the biofunction of FGF13 may also be relevant to the pathogenesis of other FGF13- and Parkin-associated diseases.

Macrophage-specific FGF12 promotes liver fibrosis progression in mice.

BACKGROUND AND AIMS: Chronic liver diseases are associated with the development of liver fibrosis. Without treatment, liver fibrosis commonly leads to cirrhosis and HCC. FGF12 is an intracrine factor belonging to the FGF superfamily, but its role in liver homeostasis is largely unknown. This study aimed to investigate the role of FGF12 in the regulation of liver fibrosis. APPROACH AND RESULTS: FGF12 was up-regulated in bile duct ligation (BDL)-induced and CCL 4 -induced liver fibrosis mouse models. Expression of FGF12 was specifically up-regulated in nonparenchymal liver cells, especially in hepatic macrophages. By constructing myeloid-specific FGF12 knockout mice, we found that deletion of FGF12 in macrophages protected against BDL-induced and CCL 4 -induced liver fibrosis. Further results revealed that FGF12 deletion dramatically decreased the population of lymphocyte antigen 6 complex locus C high macrophages in mouse fibrotic liver tissue and reduced the expression of proinflammatory cytokines and chemokines. Meanwhile, loss-of-function and gain-of-function approaches revealed that FGF12 promoted the proinflammatory activation of macrophages, thus inducing HSC activation mainly through the monocyte chemoattractant protein-1/chemokine (C-C motif) receptor 2 axis. Further experiments indicated that the regulation of macrophage activation by FGF12 was mainly mediated through the Janus kinase-signal transducer of activators of transcription pathway. Finally, the results revealed that FGF12 expression correlates with the severity of fibrosis across the spectrum of fibrogenesis in human liver samples. CONCLUSIONS: FGF12 promotes liver fibrosis progression. Therapeutic approaches to inhibit macrophage FGF12 may be used to combat liver fibrosis in the future.

δ-Catenin Requirement in Keratinocyte Proliferation and DNA Repair Identifies a Therapeutic Target for Photoaging.

Skin photoaging is a complicated pathological process and is mainly due to UV irradiation, especially UVB irradiation. Damage induction by UVB is a complex process, involving intricate molecular mechanisms. The formation of bulky photoproducts in the DNA globally affects transcription and splicing and results in the dysfunction of keratinocytes. In this study, we show that δ-catenin is predominantly distributed in keratinocytes of the skin epidermis and functionally accelerates cell proliferation and DNA repair. Ex vivo protein profiling reveals that δ-catenin upregulates the phosphorylation of RSK2Ser-227 by enhancing the interaction between PDK1 and RSK2 and thereby induces the nuclear accumulation of YB1 to promote proliferation and DNA repair. Moreover, δ-catenin overexpression induces in vivo keratinocyte proliferation and DNA repair in UVB-irradiated mouse skin. Notably, acidic fibroblast GF/FGFR1 is identified as one of the key upstream signalings of δ-catenin by inducing δ-catenin stabilization. The involvement of δ-catenin in keratinocyte proliferation and DNA repair may suggest δ-catenin as a target for the treatment of UVB damage.

CK2 blockade alleviates liver fibrosis by suppressing activation of hepatic stellate cells via the Hedgehog pathway.

BACKGROUND AND PURPOSE: Liver fibrosis is a serious cause of morbidity and mortality worldwide characterized by accumulation of extracellular matrix produced by hepatic stellate cells (HSCs). The protein kinase CK2 is a pro-survival kinase overexpressed in human tumours. However, the biological role of CK2 in liver fibrosis is largely unknown. We aimed to investigate the mechanism by which CK2 promotes liver fibrosis. EXPERIMENTAL APPROACH: In vitro, LX-2 cells were stimulated with transforming growth factor-ß (TGF-ß). HSCs were also isolated for research. In vivo, the adeno-associated virus AAV-sh-csnk2a1 was used to knockdown CK2α specifically in HSCs, and CX-4945 was used to pharmacologically inhibit the enzymatic activity of CK2 in murine models of fibrosis induced by carbon tetrachloride (CCl4 ) and a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Histological and biochemical analyses were performed to study the involvement of CK2 in regulation of fibrogenic and fibrolytic factors as well as activation properties of HSCs. KEY RESULTS: HSC-specific genetic invalidation of CK2α or pharmacological inhibition of CK2 protected mice treated with CCl4 or fed a DDC diet against liver fibrosis and HSC accumulation. Mechanistically, CK2α, which bound to Smoothened (SMO), was a positive regulator of the Hedgehog signal transduction pathway. CK2 prevented ubiquitination and proteasomal degradation of SMO, which was abolished by knockdown of CK2α or pharmacological inhibition of CK2. CONCLUSIONS AND IMPLICATIONS: CK2 activation is critical to sustain the activated and fibrogenic phenotype of HSCs via SMO stabilization. Therefore, inactivation of CK2 by CX-4945 may be of therapeutic interest for liver fibrotic diseases.

Fibroblast growth factor 7 alleviates myocardial infarction by improving oxidative stress via PI3Kα/AKT-mediated regulation of Nrf2 and HXK2.

Acute myocardial infarction (MI) triggers oxidative stress, which worsen cardiac function, eventually leads to remodeling and heart failure. Unfortunately, effective therapeutic approaches are lacking. Fibroblast growth factor 7 (FGF7) is proved with respect to its proliferative effects and high expression level during embryonic heart development. However, the regulatory role of FGF7 in cardiovascular disease, especially MI, remains unclear. FGF7 expression was significantly decreased in a mouse model at 7 days after MI. Further experiments suggested that FGF7 alleviated MI-induced cell apoptosis and improved cardiac function. Mechanistic studies revealed that FGF7 attenuated MI by inhibiting oxidative stress. Overexpression of FGF7 actives nuclear factor erythroid 2-related factor 2 (Nrf2) and scavenging of reactive oxygen species (ROS), and thereby improved oxidative stress, mainly controlled by the phosphatidylinositol-3-kinase α (PI3Kα)/AKT signaling pathway. The effects of FGF7 were partly abrogated in Nrf2 deficiency mice. In addition, overexpression of FGF7 promoted hexokinase2 (HXK2) and mitochondrial membrane translocation and suppressed mitochondrial superoxide production to decrease oxidative stress. The role of HXK2 in FGF7-mediated improvement of mitochondrial superoxide production and protection against MI was verified using a HXK2 inhibitor (3-BrPA) and a HXKII VDAC binding domain (HXK2VBD) peptide, which competitively inhibits localization of HXK2 on mitochondria. Furthermore, inhibition of PI3Kα/AKT signaling abolished regulation of Nrf2 and HXK2 by FGF7 upon MI. Together, these results indicate that the cardio protection of FGF7 under MI injury is mostly attributable to its role in maintaining redox homeostasis via Nrf2 and HXK2, which is mediated by PI3Kα/AKT signaling.

Ribosomal S6 Protein Kinase 2 Aggravates the Process of Systemic Scleroderma.

Systemic sclerosis is a complex process of pathogenesis, and the contributions of inherited genes, infections, and chemicals remain largely unknown. In this study, we showed that p90 ribosomal S6 protein kinase 2 (RSK2) was selectively upregulated in fibrotic skin and fibroblasts treated with the profibrotic cytokine TGF-ß. Moreover, knockout of Rsk2 specifically in skin fibroblasts or pharmacological inhibition of RSK2 attenuated skin fibrosis in a mouse model. Mechanistically, RSK2 directly interacted with glycogen synthase kinase 3ß in vivo and in vitro and thereby induced phosphorylation of glycogen synthase kinase 3ß at Ser9 to inhibit ubiquitination and degradation of GLI1, which promoted fibroblast differentiation and skin fibrosis. Consequently, RSK2 plays an important role in the dermal skin of systemic sclerosis. These findings provided a potential therapeutic target for systemic sclerosis.

Fibroblast growth factor 10 protects against UVB-induced skin injury by activating the ERK/YAP signalling pathway.

OBJECTIVES: Ultraviolet light B (UVB) irradiation can induce skin injury and result in keratinocytes proliferation inhibition. However, the molecular understanding of the repair during UVB-induced cell proliferation inhibition remains poorly understood. The purpose of this study was to explore the role and potential mechanism of FGF10 in promoting keratinocytes cell cycle and proliferation after UVB injury. MATERIALS AND METHODS: Expression of FGF10 protein was analysed in skin treated with UVB radiation by immunohistochemistry. The proliferation potential was examined by Immunofluorescence, Western Blot and RT-PCR under UVB radiation, treated with FGF10 protein or overexpression of FGF10 using adeno-associated virus. CCK8 kit was used to further detect cell proliferation ability. RESULTS: We found that FGF10 is highly expressed in skin treated with UVB. Overexpression of FGF10 has a protective effect against UVB-induced skin damage by balancing epidermal thickness and enhancing epidermal keratinocytes proliferation. Importantly, FGF10 is found to alleviate UVB-induced downregulation of YAP activity, then promoting keratinocytes proliferation. Disruption of YAP function, either with the small molecule YAP inhibitor Verteporfin (VP) or YAP small-interfering RNA (siRNA), largely abolishes the protective activity of FGF10 on epidermal keratinocytes proliferation. Meanwhile, disruption of ERK kinase (MEK) activity with U0126 or ERK siRNA hinder the positive influence of FGF10 on UVB-induced skin injury. CONCLUSION: FGF10 promotes epidermal keratinocytes proliferation during UVB-induced skin injury in an ERK/YAP-dependent manner.

Suppression of Cutibacterium acnes-Mediated Inflammatory Reactions by Fibroblast Growth Factor 21 in Skin.

Cutibacterium acnes (C. acnes) is a common commensal bacterium that is closely associated with the pathogenesis of acne. Fibroblast growth factor 21 (FGF21), as a favorable regulator of glucose and lipid metabolism and insulin sensitivity, was recently shown to exert anti-inflammatory effects. The role and mechanism of FGF21 in the inflammatory reactions induced by C. acnes, however, have not been determined. The present study shows that FGF21 in the dermis inhibits epidermal C. acnes-induced inflammation in a paracrine manner while it functions on the epidermal layer through a receptor complex consisting of FGF receptor 1 (FGFR1) and ß-Klotho (KLB). The effects of FGF21 in heat-killed C. acnes-induced HaCaT cells and living C. acnes-injected mouse ears were examined. In the presence of C. acnes, FGF21 largely counteracted the activation of Toll-like receptor 2 (TLR2), the downstream nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways induced by C. acnes. FGF21 also significantly reduced the expression of proinflammatory cytokines, including interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor (TNF)-α. Taken together, these findings indicate that FGF21 suppresses C. acnes-induced inflammation and might be used clinically in the management and treatment of acne.

FGF6 promotes cardiac repair after myocardial infarction by inhibiting the Hippo pathway.

OBJECTIVES: Myocardial infarction (MI) commonly occurs in patients with coronary artery disease and have high mortality. Current clinical strategies for MI still limited to reducing the death of myocardial cells but failed to replace these cells. This study aimed to investigate the role of fibroblast growth factor 6 (FGF6) in enhancing the proliferative potential of cardiomyocytes (CMs) after ischemic injury via the Hippo pathway. MATERIALS AND METHODS: Expression of FGF6 protein was analysed in mice with MI induced by ligation of the left anterior descending coronary artery. Activation of the Hippo pathway and the proliferation potential were examined in ischemic CMs, treated with FGF6 protein or transfected with an adeno-virus carrying FGF6 sh-RNA. Immunofluorescence staining and western blotting were performed to assess the relationship between FGF6 and the Hippo pathway. RESULTS: We found that FGF6 expression was significantly increased in the MI mouse model. Knockdown of FGF6 synthesis resulted in poorer heart function after MI. By contrast, treatment with recombinant human FGF6 protein improved heart function, reduced infarct size, and promoted cardiac repair. Additionally, FGF6 restrains the activation of the Hippo pathway and subsequently promotes nuclear accumulation of YAP. This was largely counteracted by treatment with extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor U0126. CONCLUSION: FGF6 inhibits the Hippo pathway via ERK1/2, and facilitates nuclear translocation of YAP, and thereby promotes cardiac repair after MI.

Fibroblast growth factor 20 attenuates pathological cardiac hypertrophy by activating the SIRT1 signaling pathway.

Cardiac hypertrophy occurs initially in response to an increased cardiac load as a compensatory mechanism to maintain cardiac output. However, sustained pathological hypertrophy can develop into heart failure and cause sudden death. Fibroblast growth factor 20 (FGF20) is a member of the fibroblast growth factor family, which involved in apoptosis, aging, inflammation, and autophagy. The precise function of FGF20 in pathological cardiac hypertrophy is unclear. In this study, we demonstrated that FGF20 was significantly decreased in response to hypertrophic stimulation. In contrast, overexpression of FGF20 protected against pressure overload-induced cardiac hypertrophy. Mechanistically, we found that FGF20 upregulates SIRT1 expression, causing deacetylation of FOXO1; this effect promotes the transcription of downstream antioxidant genes, thus inhibits oxidative stress. In content, the anti-hypertrophic effect of FGF20 was largely counteracted in SIRT1-knockout mice, accompanied by an increase in oxidative stress. In summary, our findings reveal a previously unknown protective effect of FGF20 on pathological cardiac hypertrophy by reducing oxidative stress through activation of the SIRT1 signaling pathway. FGF20 is a potential novel molecular target for preventing and treating pressure overload-induced myocardial injury.

Fibroblast growth factor 18 attenuates liver fibrosis and HSCs activation via the SMO-LATS1-YAP pathway.

Liver fibrosis, which is characterized by excessive accumulation of extracellular matrix (ECM) primarily produced by hepatic stellate cells (HSCs), can eventually lead to cirrhosis. Fibroblast growth factor 18 (FGF18) mediates various biological activities. However, the precise role of FGF18 in the pathological process of liver fibrosis and the underlying mechanisms have not been elucidated. In this study, we found that FGF18 was markedly upregulated in carbon tetrachloride (CCl4)-induced fibrotic mouse liver tissues and transforming growth factor ß (TGF-ß) stimulated LX-2 cells. Furthermore, our studies demonstrated that overexpression of FGF18 in the liver significantly alleviated CCl4-induced fibrosis and inhibited the activation of HSCs, while exacerbated by HSC-specific deletion of FGF18. Mechanistically, FGF18 treatment dramatically activated Hippo signaling pathway by suppressing smoothened (SMO) both in vivo and in vitro. Moreover, the interaction between SMO and LATS1 was crucial for the FGF18 induced protective effects. In conclusion, these results indicated that FGF18 attenuates liver fibrosis at least partially via the SMO-LATS1-YAP signaling pathway and therefore may be a potential therapeutic target for liver fibrosis.

FGF21 promotes migration and differentiation of epidermal cells during wound healing via SIRT1-dependent autophagy.

BACKGROUND AND PURPOSE: Migration and differentiation of epidermal cells are essential for epidermal regeneration during wound healing. Fibroblast growth factor 21 (FGF21) plays key roles in mediating a variety of biological activities. However, its role in skin wound healing remains unknown. EXPERIMENTAL APPROACH: Fgf21 knockout (Fgf21 KO) mice were used to determine the effect of FGF21 on wound healing. The source of FGF21 and its target cells were determined by immunohistochemistry, immunoblotting, and ELISA assay. Moreover, Sirt1flox/flox and Atg7flox/flox mice were constructed and injected with the epidermal-specific Cre virus to elucidate the underlying mechanisms. Migration and differentiation of keratinocytes were evaluated in vitro by cell scratch assays, immunofluorescence, and qRT-RCR. The effects were further assessed when SIRT1, ATG7, ATG5, BECN1, and P53 were silenced. Interactions between SIRT1 and autophagy-related genes were assessed using immunoprecipitation assays. KEY RESULTS: FGF21 was active in fibroblasts and promoted migration and differentiation of keratinocytes following injury. After wounding, SIRT1 expression and autophagosome synthesis were lower in Fgf21 KO mice. Depletion of ATG7 in keratinocytes counteracted the FGF21-induced increases in migration and differentiation, suggesting that autophagy is required for the FGF21-mediated pro-healing effects. Furthermore, epithelial-specific Sirt1 knockout abolished the FGF21-mediated improvements of autophagy and wound healing. Silencing of SIRT1 in keratinocytes, which decreased deacetylation of p53 and autophagy-related proteins, revealed that FGF21-induced autophagy during wound healing was SIRT1-dependent. CONCLUSIONS AND IMPLICATIONS: FGF21 is a key regulator of keratinocyte migration and differentiation during wound healing. FGF21 may be a novel therapeutic target to accelerate would healing.

Phosphorylation of α-CateninS641 Suppresses the NF-κB Pathway in Fibroblasts to Activate Skin Wound Repair.

Skin wound healing is a complex process involving intricate molecular mechanisms that remain unknown. Restoration of homeostasis after wounding requires the remodeling function of fibroblasts. In this study, we show that phosphorylation of α-cateninS641 was upregulated in fibroblasts during wounding, which accelerated their proliferation and migration to restore the skin barrier. At the wound edge, phosphorylated α-cateninS641 stabilized IκBα and thereby impaired the expression of NF-κB target genes to promote proliferation and migration of fibroblasts. Mechanically, phosphorylated α-cateninS641 blocked K48-linked polyubiquitination and proteasomal degradation of IκBα. Moreover, we also showed that EGF/EGFR/CK2α functioned as key upstream signaling of α-catenin by phosphorylating α-catenin at S641. Wound repair was significantly disrupted in the skin of mice in which α-catenin phosphorylation and CK2α kinase activity were perturbed in fibroblasts. These findings provide insights into the molecular control of fibroblast proliferation and migration in response to wounding and identify potential targets for the treatment of defective wound repair.

bFGF-mediated phosphorylation of δ-catenin increases its protein stability and the ability to induce the nuclear redistribution of ß-catenin.

Recently, we have shown that δ-catenin strengthened the epidermal growth factor receptor (EGFR)/Erk1/2 signaling pathway through the association between EGFR and δ-catenin. Now, we further analyzed the correlation between basic fibroblast growth factor (bFGF)/fibroblast growth factor receptor 1 (FGFR1) and δ-catenin in prostate cancer and investigated the molecular mechanism underlying the role of bFGF/FGFR1 modulation in CWR22Rv-1 (Rv-1) cells. Here, we demonstrated that bFGF phosphorylated the tyrosine residues of δ-catenin in Rv-1 cells and further proved that the bFGF mediated FGFR1/δ-catenin tyrosine phosphorylation was time dependent. Furthermore, we demonstrated that bFGF stabilized the expression of δ-catenin through weakening its association with GSK3ß and enhancing its stability to induce ß-catenin into the nuclear by strengthening the processing of E-cadherin. In a word, these results indicated that bFGF/FGFR1 signaling pathway could enhance the tumor progression of prostate cancer via δ-catenin.