In 2000, investigators discovered Tribbles, a Drosophila protein that coordinates morphogenesis by inhibiting mitosis. Further work has delineated Xenopus (Xtrb2), Nematode (Nipi-3), and mammalian homologs of Drosophila tribbles, which include TRB1, TRB2, and TRB3. The sequences of tribbles homologs are highly conserved, and despite their protein kinase structure, to date they have not been shown to have kinase activity. TRB family members play a role in the differentiation of macrophages, lymphocytes, muscle cells, adipocytes, and osteoblasts. TRB isoforms also coordinate a number of critical cellular processes including glucose and lipid metabolism, inflammation, cellular stress, survival, apoptosis, and tumorigenesis. TRB family members modulate multiple complex signaling networks including mitogen activated protein kinase cascades, protein kinase B/AKT signaling, mammalian target of rapamycin, and inflammatory pathways. The following review will discuss metazoan homologs of Drosophila tribbles, their structure, expression patterns, and functions. In particular, we will focus on TRB3 function in the kidney in podocytes. This review will also discuss the key signaling pathways with which tribbles proteins interact and provide a rationale for developing novel therapeutics that exploit these interactions to provide better treatment options for both acute and chronic kidney disease. 1. Introduction In the age of personalized and targeted medical therapies [1], the treatment of both acute and chronic kidney disease (CKD) remains a formidable challenge. Our treatment options in these diseases are limited and often rely on basic immunosuppression with corticosteroids, steroid-sparing medications, and supportive measures. Both acute kidney injury [2–4] and chronic kidney disease [5–9] are associated with the activation of multiple signaling pathways, which can contribute to persistent organ injury. It is likely that therapeutics that regulate these signaling cascades can be developed to provide more effective and specific approaches for treating diverse kidney diseases. Work over the last decade has elucidated a number of novel signaling molecules that dampen the activation of potentially harmful signaling cascades. One such protein, tribbles may function at the intersection of multiple stress-activated pathways including the mammalian target of rapamycin (mTOR), endoplasmic reticulum (ER) stress, and macro-autophagy pathways. In the following review, we will first discuss metazoan homologs of Drosophila tribbles, their structure, expression patterns, and
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