Sorenson C M, Sheibani N
George M. O'Brien Kidney and Urological Diseases Center, Renal Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Dev Dyn. 1999 Aug;215(4):371-82. doi: 10.1002/(SICI)1097-0177(199908)215:4<371::AID-AJA8>3.0.CO;2-H.
Cell adhesive mechanisms which determine tissue architecture during morphogenesis are tightly regulated and have an impact on apoptosis, cell migration, proliferation, and differentiation. Bcl-2 is a death repressor that protects cells from apoptosis initiated by a variety of stimuli including loss of cell adhesion. Utilizing the kidney as a model of an organ that undergoes three-dimensional development we demonstrate that bcl-2 directly associates with paxillin. Focal adhesion kinase (FAK)(p125) and paxillin(p68) were highly expressed and tyrosine phosphorylated during development but declined to low levels following renal maturation (postnatal day 20) in normal mice. The decline in the expression of p125 FAK and p68 paxillin occurred together with an increase in specific cleavage products of lower molecular weights. Mice deficient in bcl-2 are born with renal hypoplasia and succumb to renal failure as a result of renal multicystic disease. In kidneys from postnatal day 20 bcl-2 -/- mice, tyrosine phosphorylation of p125 FAK and p68 paxillin was not down-regulated. However, the level of expression was similar to that of normal mice. These results demonstrate that the developmentally regulated expression and phosphorylation of FAK and paxillin, in the presence of bcl-2, is necessary for normal morphogenesis. The interaction of paxillin with bcl-2 during nephrogenesis may provide an alternative to integrin(s) signaling through paxillin/FAK thus bypassing the need for adhesion-mediated survival during three dimensional morphogenesis. Dev Dyn 1999;215:371-382.
在形态发生过程中决定组织结构的细胞黏附机制受到严格调控，并对细胞凋亡、迁移、增殖和分化产生影响。Bcl-2是一种死亡抑制因子，可保护细胞免受包括细胞黏附丧失在内的多种刺激引发的凋亡。利用肾脏作为经历三维发育的器官模型，我们证明Bcl-2直接与桩蛋白相关联。在发育过程中，粘着斑激酶（FAK）（p125）和桩蛋白（p68）高度表达且酪氨酸磷酸化，但在正常小鼠肾脏成熟后（出生后第20天）降至低水平。p125 FAK和p68桩蛋白表达的下降与较低分子量的特异性裂解产物增加同时发生。缺乏Bcl-2的小鼠出生时肾脏发育不全，并因肾多囊性疾病而死于肾衰竭。在出生后第20天的bcl-2 -/-小鼠的肾脏中，p125 FAK和p68桩蛋白的酪氨酸磷酸化未下调。然而，表达水平与正常小鼠相似。这些结果表明，在Bcl-2存在的情况下，FAK和桩蛋白的发育调控表达和磷酸化对于正常形态发生是必要的。在肾发生过程中桩蛋白与Bcl-2的相互作用可能为通过桩蛋白/FAK的整合素信号传导提供一种替代途径，从而在三维形态发生过程中无需黏附介导的存活。《发育动力学》1999年；215：371 - 382。
