FAM3 Cytokine-like Proteins, Their Putative Receptors and Signaling Pathways in Metabolic Diseases and Cancers

FAM3A, FAM3B, FAM3C and FAM3D are members of “family with sequence similarity 3” (FAM3) gene family, an emerging class of cytokine-like proteins with a unique structural globular beta-beta-alpha fold and distinct biological functions. With widespread expression in tissue, organs and in many cell types, their specific roles in human diseases have been the focus of much research. FAM3A acts as a positive regulator of metabolic health, typically activating canonical pro-survival and metabolic pathways. FAM3B, also called PANDER (PANcreatic DERived Factor) exerts critical physiological functions in the regulation of glycemic levels via promotion of hepatic glucose production and pancreatic beta-cell insulin secretion. FAM3C, also named ILEI (Interleukin-like EMT inducer), is involved as inducer of epithelial-mesenchymal transition (EMT) and cancer metastasis, as well as osteoblast differentiation and bone mineralization. FAM3D is a gut secreted protein and potential regulator of gastrointestinal homeostasis and microbiota-induced inflammation. Here we provide an overview of previous studies supporting that FAM3 proteins can binding to putative membrane receptors and co-partners, including Fibroblast Growth Factor Receptor (FGFR), Leukemia Inhibitory Factor Receptor (LIFR), Formyl Peptide Receptor (FPR1/2), to activate diverse downstream signaling pathways on different cellular contexts. Basic and clinical studies suggest that FAM3 family influence both obesity, diabetes, and other metabolic disorders, thus its expression may have diagnostic potential. The differential and often cancer-specific expression patterns make members of the FAM3 family promising candidates for biomarkers and therapeutic targets of some types of neoplasia.