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A Disintegrin and Metalloproteinases (ADAMs) are the principal enzymes for shedding receptor tyrosine kinase (RTK) ectodomains and ligands from the cell surface. Multiple layers of activity regulation, feedback, and catalytic promiscuity impede our understanding of context-dependent ADAM “sheddase” function and our ability to predictably target that function in disease. This study uses combined measurement and computational modeling to examine how various growth factor environments influence sheddase activity and cell migration in the invasive disease of endometriosis. We find that ADAM-10 and -17 dynamically integrate numerous signaling pathways to direct cell motility. Data-driven modeling reveals that induced cell migration is a quantitative function of positive feedback through EGF ligand release and negative feedback through RTK shedding. Although sheddase inhibition prevents autocrine ligand shedding and resultant EGF receptor transactivation, it also leads to an accumulation of phosphorylated receptors (HER2, HER4, and MET) on the cell surface, which subsequently enhances Jnk/p38 signaling. Jnk/p38 inhibition reduces cell migration by blocking sheddase activity while additionally preventing the compensatory signaling from accumulated RTKs. In contrast, Mek inhibition reduces ADAM-10 and -17 activities but fails to inhibit compensatory signaling from accumulated RTKs, which actually enhances cell motility in some contexts. Thus, here we present a sheddase-based mechanism of rapidly acquired resistance to Mek inhibition through reduced RTK shedding that can be overcome with rationally directed combination inhibitor treatment. We investigate the clinical relevance of these findings using targeted proteomics of peritoneal fluid from endometriosis patients and find growth-factor–driven ADAM-10 activity and MET shedding are jointly dysregulated with disease.

PurposeThe purpose of this study was to examine the role of fear of COVID-19 and job stress on women's turnover intentions in the hospitality industry (travel agencies). Also, the mediating role of work-family conflict was examined.Design/methodology/approachThree theoretical approaches of importance for framing issues of fear of COVID-19, job stress, work-family conflict and women's turnover intentions. Using the purposive sampling technique, the participants for the current paper were selected from the population of employees of top travel and tour operation firms in Lagos, Nigeria.FindingsFindings from the study indicate that the fear of COVID-19 and job stress was found to be positively related to work-family conflict and work-family conflict was positively related to women's turnover intentions. Work-family conflict mediates the positive relationship between fear of COVID-19 and women's turnover intentions, while against priori; the work-family conflict did not mediate the relationship between job stress and women's turnover intentions.Research limitations/implicationsOur study's findings were limited in their generalizability because they focused on a specific operating sector of tourism, travel and tour. Testing the study's model in different tourism operating sectors or mixed industries could offer better insights. A comparative study between this current context and western/non-western contexts to provide more contextual insights.Originality/valueThis study considered travel agencies (the pillar of the tourism industry) that have been understudied. The main strength of the study is its female-centric approach to uncovering the influence of the COVID-19 pandemic on hospitality employee outcomes. Specifically, the study used African females in the hospitality settings to investigate the aforementioned relationships. 10; Keywords: COVID-19; job stress; turnover intention; work-family conflict.