Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
ħ bioconsulting llc, Stillwater, MN, United States.
Curr Top Dev Biol. 2022;150:25-89. doi: 10.1016/bs.ctdb.2022.03.003. Epub 2022 Jun 11.
Paracrine cell-cell communication is central to all developmental processes, ranging from cell diversification to patterning and morphogenesis. Precise calibration of signaling strength is essential for the fidelity of tissue formation during embryogenesis and tissue maintenance in adults. Membrane-tethered ubiquitin ligases can control the sensitivity of target cells to secreted ligands by regulating the abundance of signaling receptors at the cell surface. We discuss two examples of this emerging concept in signaling: (1) the transmembrane ubiquitin ligases ZNRF3 and RNF43 that regulate WNT and bone morphogenetic protein receptor abundance in response to R-spondin ligands and (2) the membrane-recruited ubiquitin ligase MGRN1 that controls Hedgehog and melanocortin receptor abundance. We focus on the mechanistic logic of these systems, illustrated by structural and protein interaction models enabled by AlphaFold. We suggest that membrane-tethered ubiquitin ligases play a widespread role in remodeling the cell surface proteome to control responses to extracellular ligands in diverse biological processes.
旁分泌细胞间通讯是所有发育过程的核心，从细胞多样化到模式形成和形态发生。在胚胎发生过程中组织形成的保真度和成年组织维持中，信号强度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准对于信号受体在细胞表面的丰度的精确校准。膜结合泛素连接酶可以通过调节细胞表面信号受体的丰度来控制靶细胞对分泌配体的敏感性。我们讨论了信号转导中这一新兴概念的两个例子：（1）跨膜泛素连接酶 ZNRF3 和 RNF43，它们响应 R 分泌蛋白配体调节 WNT 和骨形态发生蛋白受体的丰度；（2）膜募集的泛素连接酶 MGRN1，它控制 Hedgehog 和黑素皮质素受体的丰度。我们专注于这些系统的机制逻辑，通过 AlphaFold 提供的结构和蛋白质相互作用模型来说明。我们认为，膜结合泛素连接酶在重塑细胞表面蛋白质组以控制对不同生物过程中外源配体的反应方面发挥了广泛的作用。
