Members of the Fibroblast Growth Factor Receptor Superfamily Are Proteolytically Cleaved by Two Differently Activated Metalloproteases.

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that have been associated not only with various cellular processes, such as embryonic development and adult wound healing but also enhanced tumor survival, angiogenesis, and metastatic spread. Proteolytic cleavage of these single-pass transmembrane receptors has been suggested to regulate biological activities of their ligands during growth and development, yet little is known about the proteases responsible for this process. In this study, we monitored the release of membrane-anchored FGFRs 1, 2, 3, and 4 in cell-based assays. We demonstrate here that metalloprotease-dependent metalloprotease family, ADAM10 and ADAM17. Loss- and gain-of-function studies in murine embryonic fibroblasts showed that constitutive shedding as well as phorbol-ester-induced processing of FGFRs 1, 3, and 4 is mediated by ADAM17. In contrast, treatment with the calcium ionophore ionomycin stimulated ADAM10-mediated FGFR2 shedding. Cell migration assays with keratinocytes in the presence or absence of soluble FGFRs suggest that ectodomain shedding can modulate the function of ligand-induced FGFR signaling during cell movement. Our data identify ADAM10 and ADAM17 as differentially regulated FGFR membrane sheddases and may therefore provide new insight into the regulation of FGFR functions.

Perceptions of families and healthcare providers about feeding preterm infants in the neonatal intensive care unit: protocol for a qualitative systematic review.

INTRODUCTION: The underdevelopment of preterm infants can lead to delayed progression through key early milestones. Demonstration of safe oral feeding skills, constituting proper suck-swallow reflex are requirements for discharge from the neonatal intensive care unit (NICU) to ensure adequate nutrition acquisition. Helping an infant develop these skills can be draining and emotional for both families and healthcare staff involved in the care of preterm infants with feeding difficulties. Currently, there are no systematic reviews evaluating both family and healthcare team perspectives on aspects of oral feeding. Thus, we first aim to evaluate the current knowledge surrounding the perceptions, experiences and needs of families with preterm babies in the context of oral feeding in the NICU. Second, we aim to evaluate the current knowledge surrounding the perceptions, experiences and needs of healthcare providers (physicians, advanced practice providers, nurses, dietitians, speech-language pathologists and occupational therapists) in the context of oral feeding in the NICU. METHODS AND ANALYSIS: A literature search will be conducted in multiple electronic databases from their inception, including PubMed, CINHAL, Embase, the Cochrane Central Register for Controlled Trials and PsycINFO. No restrictions will be applied based on language or data of publication. Two authors will screen the titles and abstracts and then review the full text for the studies' inclusion in the review. The data will be extracted into a pilot-tested data collection sheet by three independent authors. To evaluate the quality, reliability and relevance of the included studies, the Critical Appraisal Skills Programme checklist will be used. The overall evidence will be assessed using the Grading of Recommendation Assessment, Development and Evaluation criteria. We will report the results of the systematic review by following the Enhancing Transparency in Reporting the synthesis of Qualitative research checklist. ETHICS AND DISSEMINATION: Ethical approval of this project is not required as this is a systematic review using published and publicly available data and will not involve contact with human subjects. Findings will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42023479288.

Functional Distinctions of Endometrial Cancer-Associated Mutations in the Fibroblast Growth Factor Receptor 2 Gene.

Functional analysis of somatic mutations in tumorigenesis facilitates the development and optimization of personalized therapy for cancer patients. The fibroblast growth factor receptor 2 (FGFR2) gene is frequently mutated in endometrial cancer (EC), but the functional implications of FGFR2 mutations in cancer development remain largely unexplored. In this study, we introduced a reliable and readily deployable screening method to investigate the effects of FGFR2 mutations. We demonstrated that distinct mutations in FGFR2 can lead to differential downstream consequences, specifically affecting a disintegrin- and metalloprotease 17 (ADAM17)-dependent shedding of the epidermal growth factor receptor (EGFR) ligand heparin-binding EGF-like growth factor (HB-EGF) and phosphorylation of mitogen-activated protein kinases (MAPKs). Furthermore, we showed that the distribution of mutations within the FGFR2 gene can influence their oncogenic effects. Together, these findings provide important insights into the complex nature of FGFR2 mutations and their potential implications for EC. By unraveling the distinct effects of different mutations, our study contributes to the identification of personalized treatment strategies for patients with FGFR2-mutated cancers. This knowledge has the potential to guide the development of targeted therapies that specifically address the underlying molecular alterations associated with FGFR2 mutations, ultimately improving patient outcomes in EC and potentially other cancer types characterized by FGFR2 mutations.

Loss of RHBDF2 results in an early-onset spontaneous murine colitis.

Inflammatory bowel disease (IBD) is a heterogeneous group of inflammation-mediated pathologies that include Crohn's disease and ulcerative colitis and primarily affects the colon and small intestine. Previous studies have shown that a disintegrin and metalloprotease (ADAM) 17, a membrane-bound sheddase, capable of cleaving the proinflammatory cytokine TNF and epidermal growth factor receptor ligands, plays a critical role in maintaining gut homeostasis and modulating intestinal inflammation during IBD. Rhomboid 5 homolog 2 (RHBDF2), a catalytically inactive member of the rhomboid family of intramembrane serine proteases, was recently identified as a crucial regulator of ADAM17. Here, we assessed the role of RHBDF2 in the development of colitis in the context of IL10 deficiency. Il10-/- /Rhbdf2-/- mice developed spontaneous colitis and experienced severe weight loss starting at 8 wk of age, without the need for exogenous triggers. Severity of disease pathology in Il10-/- /Rhbdf2-/- mice correlated with a dysbiotic gut microbiota and elevated Th1-associated immune responses with increased interferon gamma and IL2 production. In addition, Il10-/- /Rhbdf2-/- mice failed to maintain their epithelial cell homeostasis, although the intestinal epithelial barrier of Rhbdf2-/- mice is intact and loss of Rhbdf2 did not significantly exacerbate sensitivity to dextran sulfate sodium-induced colitis, suggesting differences in the underlying disease pathway of intestinal inflammation in this model. Taken together, our results demonstrate a critical regulatory role for RHBDF2 in the maintenance of the unique homeostasis between intestinal microbiota and host immune responses in the gut that is dysregulated during the pathogenesis of IBD.