Figure 4.

Members of the BMP signaling cascade with a role in CAKUT. Proteins encoded by genes that, if mutated, cause murine CAKUT are outlined in red, and proteins highlighted in yellow constitute causes of isolated and/or syndromic manifestations of human CAKUT (Supplemental Table 4). BMPs act as ligands for two classes of transmembrane serine-threonine-kinase receptors on the surface of the corresponding effector cells (e.g., bone morphogenic protein receptor type 1A [BMPR1A] and BMPR2).¹⁵⁵ After activated, these receptors initiate intracellular signaling cascades, including canonical SMAD signaling and noncanonical signaling (e.g., via mitogen-activated protein kinase [MAPK]), which eventually result in increased expression of distinct target genes in the cell nucleus.^175,176 The cellular consequences of BMP signaling depend on the location and local concentration of the BMP ligand.¹⁷⁷ The availability of ligands for receptor binding is regulated by diverse intra- and extracellular antagonists and agonists of BMP and includes, for example, Gremlin 1 (GREM1), Follistatin (FST), and bone morphogenic protein binding to the endothelial regulator (BMPER).^178–180 Please note that, BMPR2, although depicted in the figure, has not been implicated in the pathogenesis of CAKUT to date. CRIM1, cysteine-rich transmembrane bone morphogenic protein regulator 1; CTDNEP1, CTD nuclear envelope phosphatase 1; GPC3, Glypican 3.