Accelerated re-epithelialization in<i>Dpr2</i>-deficient mice is associated with enhanced response to TGFβ signaling

Meng, Fanwei; Chen, Xuan; Yang, Leilei; Hou, Ning; Yang, Xiao; Meng, Anming

doi:10.1242/jcs.032417

Cited by 35 publications

(49 citation statements)

References 51 publications

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“…Four 4-mm full-thickness cutaneous biopsy punch wounds were generated in the back skin of the gene-deficient mice and control littermates (16). The mice were killed at different time points (3, 5, 7 days) after injury and wounds were excised including 2 mm of the epidermal margins for RNA or protein isolation.…”

Section: Methodsmentioning

confidence: 99%

Delayed Re-epithelialization in Ppm1a Gene-deficient Mice Is Mediated by Enhanced Activation of Smad2

Yang

Teng²,

Hou³

et al. 2011

Journal of Biological Chemistry

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Background:The in vivo function of Ppm1a in mammals remains unknown. Results: Mice lacking Ppm1a developed normally but showed delayed re-epithelialization with retarded keratinocyte migration caused by overactivation of Smad2 during cutaneous wound healing. Conclusion: Ppm1a, through suppressing Smad2-mediated signaling, plays a critical role in re-epithelialization. Significance: We provided the first direct and critical genetic evidence of the in vivo role of Ppm1a.

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Section: Methodsmentioning

confidence: 99%

Delayed Re-epithelialization in Ppm1a Gene-deficient Mice Is Mediated by Enhanced Activation of Smad2

Yang

Teng²,

Hou³

et al. 2011

Journal of Biological Chemistry

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“…We have also demonstrated that zebrafish and mouse Dpr2 inhibit transforming growth factor-␤ (TGF-␤)/Nodal signaling by promoting degradation of their type I receptors (25,29). Studies with knock-out mouse models revealed that Dpr2 functions in reepithelialization of skin wounds by attenuating TGF-␤ signaling (30), whereas Dpr1 plays a critical role in PCP signaling during development of mice (31,32). Dpr1 regulates morphogenesis of the primitive streak by controlling Vangl2 activity (31) or modulates PCP signaling in early embryos by controlling the level and the cellular localization of Dvl proteins (32).…”

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confidence: 99%

Protein Kinase A-mediated 14-3-3 Association Impedes Human Dapper1 to Promote Dishevelled Degradation

Hua

Martin

et al. 2011

Journal of Biological Chemistry

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Wnt signaling regulates embryo development and tissue homeostasis, and its deregulation leads to an array of diseases, including cancer. Dapper1 has been shown to be a key negative regulator of Wnt signaling. However, its function and regulation remain poorly understood. In this study, we report that 14-3-3␤ interacts with human Dapper1 (hDpr1). The interaction is dependent on protein kinase A (PKA)-mediated phosphorylation of hDpr1 at Ser-237 and Ser-827. 14-3-3␤ binding attenuates the ability of hDpr1 to promote Dishevelled (Dvl) degradation, thus enhancing Wnt signaling. We further provide evidence that PKA-mediated Dpr1 phosphorylation may contribute to growth and tumor formation of colon cancer Caco2 cells. Finally, we show that cyclooxygenase-2 expression and PKA activation are positively correlated with Dvl protein levels in colon cancer samples. Together, our findings establish a novel layer of regulation of Wnt signaling by PKA via the 14-3-3-Dpr1-Dvl axis.Both the canonical and noncanonical Wnt signaling pathways are evolutionarily conserved and play key roles in development and disease (1-4). The canonical Wnt/␤-catenin pathway is initiated by Wnt ligands binding to their receptors Frizzled and low density lipoprotein receptor-related protein 5/6 (LRP5/6), which leads to the cytosolic accumulation of ␤-catenin by disrupting the ␤-catenin destruction complex consisting of Axin, adenomatous polyposis coli (APC), 3 and glycogen synthase kinase 3␤ (GSK3␤). Accumulated ␤-catenin translocates into the nucleus and activates the transcription of Wnt target genes in collaboration with the transcription factor T cell factor/lymphoid enhancer factor (5, 6). In addition to the planar cell polarity (PCP) pathway, which regulates cell polarity and convergent extension, noncanonical Wnt signaling can also be mediated by Ca 2ϩ and other signaling molecules (7,8).Dishevelled (Dvl) is the central player in both the canonical and noncanonical Wnt signaling pathways, serving as a scaffold protein bridging . Dvl can also function in the nucleus (11), where it cooperates with c-Jun, ␤-catenin, and TCF to regulate Wnt target gene transcription (12). Therefore, like many other signaling proteins, Dvl activity is tightly regulated. It can be phosphorylated by casein kinase 2 (13). The stability of Dvl proteins is regulated by an array of proteins, including Dapper1/Dact1, Inversin, NEDL1, Prickle-1, and KLHL12 (14 -17). Our recent work also showed that Dvl protein is ubiquitinated by pVHL-containing E3 ubiquitin ligase and can be regulated by autophagy (18). In addition, altered Dvl expression has been implicated in oncogenesis. Dvl is overexpressed in prostate cancer, non-small cell lung cancer, mesothelioma, and other cancers, and its up-regulation has been indicated to be correlated with activation of Wnt/␤-catenin signaling (19 -21).Dapper1 (Dpr1), also called Dact1, as a Dvl-interacting protein, is a negative regulator of both canonical and noncanonical Wnt signaling (14,22). Three Dpr family members, Dpr1, Dpr2, and Dpr...

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“…which may contribute to the epidermal remodeling [42,44] as well as to EMT [8,37,45]. Activated matrix metalloproteinase and destabilization of adherens junctions of PDPN-expressing cells might also be interpreted as the epidermal remodeling process [9,46].…”

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confidence: 99%

Podoplanin expression in wound and hyperproliferative psoriatic epidermis: Regulation by TGF-β and STAT-3 activating cytokines, IFN-γ, IL-6, and IL-22

Honma

Minami-Hori

Takahashi

et al. 2012

Journal of Dermatological Science

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Background Podoplanin (PDPN)/T1/aggrus/PA2.26 antigen, a transmembranous glycoprotein, is a well-known lymphatic endothelial marker. Recent evidence indicates that PDPN is also expressed in keratinocytes especially of sebaceous glands.Objective To verify expression-pattern and the regulatory mechanism of PDPN in human epidermal keratinocytes Methods PDPN-expression pattern was analyzed in normal and psoriatic epidermis by immunostaining. The regulatory mechanism of PDPN-expression of keratinocytes by cytokines was analyzed using specific inhibitors, siRNA, and adenoviral shRNA of signaling pathways.Results In normal skin, PDPN was expressed on the basal cell layer of sebaceous glands and on the outer root sheath of hair follicles. While no expression was detected in the normal interfollicular epidermis, PDPN was detected in the basal cell layer of wound and hyperproliferative psoriatic epidermis, where the granular layer is lacking.

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Accelerated re-epithelialization inDpr2-deficient mice is associated with enhanced response to TGFβ signaling

Cited by 35 publications

References 51 publications

Delayed Re-epithelialization in Ppm1a Gene-deficient Mice Is Mediated by Enhanced Activation of Smad2

Delayed Re-epithelialization in Ppm1a Gene-deficient Mice Is Mediated by Enhanced Activation of Smad2

Protein Kinase A-mediated 14-3-3 Association Impedes Human Dapper1 to Promote Dishevelled Degradation

Podoplanin expression in wound and hyperproliferative psoriatic epidermis: Regulation by TGF-β and STAT-3 activating cytokines, IFN-γ, IL-6, and IL-22

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