Browsing by Subject "FABP4"
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Item Identification of Putative Fatty Acid Binding Protein 4 Receptors on Breast Cancer Epithelial Cells(2023-05) Chen, DongmeiFatty acid binding protein 4 (FABP4) is a small 15-kDa cytoplasmic lipid carrier protein regulating fatty acid trafficking and metabolism. It is one of the most abundant proteins in mature adipocytes and can be secreted into the extracellular environment upon lipolytic stimulus, functioning as an adipokine. Elevated circulating FABP4 levels have been associated with obesity-related and inflammation-related diseases. Recent studies have indicated FABPP4 as a potential biomarker in cancer diagnosis and prognosis. FABP4 upregulation or exogenous FABP4 (eFABP4) administration has been found to promote cancer growth, invasion and metastasis, while FABP4 inhibition reduced cancer progression. Understanding the molecular mechanism underlying FABP4 effects in cancer is critical for developing anticancer drugs. Although exogenous FABP4 has been found to exert pro-tumorigenic effects, there is no known FABP4 receptor that transduces its signaling into intracellular responses. Identifying a FABP4 receptor would be significant for targeting FABP4 in cancers. Furthermore, although fatty acids have been found to be essential in FABP4 function, the mechanisms explaining their collaboration remain largely unknown. This thesis aims to identify putative FABP4 receptors on cancer cell plasma membrane to understand FABP4 signaling in breast cancer cells. Our work reveals that eFABP4 binds to the extracellular domain of desmoglein 2 to mediate breast cancer epithelial cell growth via an ERK-NRF2 axis, suggesting desmoglein 2 as a FABP4 receptor. We also find that fatty acids enhance the interaction between FABP4 and desmoglein 2, which may explain why non-fatty acid binding mutants of FABP4 abolish FABP4 effects and support the role of fatty acids in FABP4 signaling. In conclusion, our findings provide new insights into the mechanism of FABP4 in the development and progression of obesity-associated cancers.Item Unconventional protein secretion from adipocytes(2018-10) Josephrajan, AjeethaEndocrine function of the adipose tissue plays a major role in maintaining energy balance and glucose homeostasis by releasing a large number of bioactive proteins. Any dysfunction of the endocrine function of the adipose tissue caused due to obesity will initiate pathophysiological changes and hasten disease progression. In this thesis, I focus on the secretion of leaderless proteins from the primary cells of the adipose tissue, the adipocytes. This secretion process is called unconventional protein secretion (UPS) and as shown here for the first time, our results indicate that the UPS is highly regulated and a variety of proteins are secreted upon the adipocyte receiving a lipolytic stimuli. To characterize the UPS, we followed the secretion pathway of unconventionally secreted adipocyte fatty acid binding protein (FABP4). FABP4 is one of the majorly expressed protein in mature adipocytes whose intracellular function is lipid storage and trafficking. Increasing evidence indicates that FABP4 has multiple functions extracellularly and is strongly associated with metabolic disease progression. Our results elucidate the regulation and mechanism of UPS/FABP4 secretion pathway. Unraveling the role of UPS proteins in the circulation and integrating them as a systemic response will be central to our understanding of the balance between healthy and unhealthy states. Such a study will be more insightful in predicting metabolic diseases than analyzing different individual marker proteins in the blood stream at a time for various pathologies.