Rabbit Anti-Human ErbB3 (phospho Tyr1289) monoclonal antibody, clone F.460.4

A primary pathological feature of polycystic kidney disease (PKD) is the hyperproliferation of epithelial cells in renal tubules, resulting in formation of fluid-filled cysts. The proliferative aspects of the two major forms of PKD-autosomal dominant PKD (ADPKD), which arises from mutations in the polycystins PKD1 and PKD2, and autosomal recessive PKD (ARPKD), which arises from mutations in PKHD1-has encouraged investigation into protein components of the core cell proliferative machinery as potential drivers of PKD pathogenesis. In this review, we examine the role of signaling by ERBB proteins and their effectors, with a primary focus on ADPKD. The ERBB family of receptor tyrosine kinases (EGFR/ERBB1, HER2/ERBB2, ERBB3, and ERBB4) are activated by extracellular ligands, inducing multiple pro-growth signaling cascades; among these, activation of signaling through the RAS GTPase, and the RAF, MEK1/2, and ERK1/2 kinases enhance cell proliferation and restrict apoptosis during renal tubuloepithelial cyst formation. Characteristics of PKD include overexpression and mis-localization of the ERBB receptors and ligands, leading to enhanced activation and increased activity of downstream signaling proteins. The altered regulation of ERBBs and their effectors in PKD is influenced by enhanced activity of SRC kinase, which is promoted by the loss of cytoplasmic Ca2+ and an increase in cAMP-dependent PKA kinase activity that stimulates CFTR, driving the secretory phenotype of ADPKD. We discuss the interplay between ERBB/SRC signaling, and polycystins and their depending signaling, with emphasis on thes changes that affect cell proliferation in cyst expansion, as well as the inflammation-associated fibrogenesis, which characterizes progressive disease. We summarize the current progress of preclinical and clinical trials directed at inhibiting this signaling axis, and discuss potential future strategies that may be productive for controlling PKD.

In human mutant BRAF melanoma cells, the stemness transcription factor FOXD3 is rapidly induced by inhibition of ERK1/2 signaling and mediates adaptive resistance to RAF inhibitors. However, the mechanism underlying ERK signaling control of FOXD3 expression remains unknown. Here we show that SOX10 is both necessary and sufficient for RAF inhibitor-induced expression of FOXD3 in mutant BRAF melanoma cells. SOX10 activates the transcription of FOXD3 by binding to a regulatory element in FOXD3 promoter. Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity. Finally, depletion of SOX10 sensitizes mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo. Thus, our work discovers a novel phosphorylation-dependent regulatory mechanism of SOX10 transcription activity and completes an ERK1/2/SOX10/FOXD3/ERBB3 axis that mediates adaptive resistance to RAF inhibitors in mutant BRAF melanoma cells.