Protein Ser/Thr phosphatase-6 is required for maintenance of E-cadherin at adherens junctions.
Protein Ser/Thr phosphatase-6 is required for maintenance of E-cadherin at adherens junctions.
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DOI：
10.1186/1471-2121-14-42
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发表时间：
2013-09-25
期刊：
影响因子：
--
通讯作者：
Brautigan DL
中科院分区：
文献类型：
--
作者：
Ohama T;Wang L;Griner EM;Brautigan DL
上皮组织依赖于e -钙粘蛋白的细胞间二聚化，而e -钙粘蛋白的缺失是多种人类疾病中上皮向间质转化的关键。信号通路通过酪蛋白激酶等激酶对细胞质区域的磷酸化调节e -钙粘蛋白的功能和细胞分布，但所涉及的蛋白磷酸酶尚未确定。本研究表明，蛋白丝氨酸/苏氨酸磷酸酶-6催化亚基（PP6c）在上皮组织中表达，其mRNA和蛋白在高密度和低密度上皮细胞系中均显著上调。PP6c在粘附连接处积累，而不是紧密连接处，与没有典型SAPS亚基的E-cadherin-catenin复合物共免疫沉淀，并直接与E-cadherin细胞质尾部结合。诱导shRNA敲低PP6c使E-cadherin从细胞表面分散，通过酪蛋白激酶-1的化学抑制逆转这种反应，并通过小鼠E-cadherin中Ser846的丙氨酸替代来阻止这种反应。PP6c在粘附连接中与E-cadherin结合，并且需要对抗酪蛋白激酶-1以维持E-cadherin的细胞表面定位。在高密度上皮细胞中，有反馈信号增强PP6c转录并提高蛋白水平。
Epithelial tissues depend on intercellular homodimerization of E-cadherin and loss of E-cadherin is central to the epithelial to mesenchymal transition seen in multiple human diseases. Signaling pathways regulate E-cadherin function and cellular distribution via phosphorylation of the cytoplasmic region by kinases such as casein kinases but the protein phosphatases involved have not been identified. This study shows protein Ser/Thr phosphatase-6 catalytic subunit (PP6c) is expressed in epithelial tissue and its mRNA and protein are robustly up-regulated in epithelial cell lines at high vs. low density. PP6c accumulates at adherens junctions, not tight junctions, co-immunoprecipitates with E-cadherin-catenin complexes without a canonical SAPS subunit, and associates directly with the E-cadherin cytoplasmic tail. Inducible shRNA knockdown of PP6c dispersed E-cadherin from the cell surface and this response was reversed by chemical inhibition of casein kinase-1 and prevented by alanine substitution of Ser846 in murine E-cadherin. PP6c associates with E-cadherin in adherens junctions and is required to oppose casein kinase-1 to maintain cell surface localization of E-cadherin. There is feedback signaling to enhance PP6c transcription and boost protein levels in high density epithelial cells.
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