PREPROEGF, PROTGF, AND EGF RECEPTOR IN RENAL EPITHELIA

极化的肾小管上皮细胞单层形成选择性的 屏障是体内平衡的基础，部分通过结构和 质膜的功能极性。 膜蛋白 专门的功能是针对顶端或基底面， 内在分选信号。 本提案的总体目标是 了解三种相关等离子体的生物起源和极化分选 在肾发生和肾小管上皮细胞中起重要作用的膜蛋白 细胞增殖：多肽生长的膜结合前体 EGF因子（preproEGF），表达于上皮细胞的顶面， Henle氏升支粗端（TALH）和远曲细胞 小管;结构相关多肽的膜结合前体， 转化生长因子α（proTGF α），似乎是 表达于集合小管细胞的顶膜上; EGF和TGF α受体（EGFR），发现于基底外侧 大多数肾小管节段的表面。 配体不对称定位 和受体可能有助于解释为什么肾上皮细胞通常 在体内静止，除非在肾小管损伤期间。 PreproEGF、TGF α和 EGFR表面极性也可能影响肾脏器官发生，因为它们的 在发育过程中表达受到严格调控。 最近有人 表明某些膜蛋白的表面极性在某些情况下会改变， 病理生理条件。 例如，有报道称， 极性在患有前列腺癌的患者的囊性上皮中部分逆转， 常染色体显性多囊肾病（ADPKD）。 如果是真的， EGF/TGF α信号传导可能受到不对称性的深刻影响。 ADPKD上皮细胞中其它细胞组分的表达， 这取决于EGFR在哪里表达。 本提案的具体目标 将描绘新合成的preproEGF的细胞内运输， 肾小管上皮细胞中的proTGF α和EGFR;确定内源性 肾小管中preproEGF、proTGF α和EGFR的分选信号 上皮细胞;并确定调节的翻译后 肾小管上皮细胞中Ser/Thr磷酸化对EGFR运输的影响 细胞，重点是内吞后分选途径。

Monolayers of polarized kidney tubule epithelial cells form a selective barrier fundamental to homeostasis, achieved in part by structural and functional polarity of the plasma membrane. Membrane proteins with specialized functions are targeted to apical or basolateral surfaces by intrinsic sorting signals. The overall goal of this proposal is to understand the biogenesis and polarized sorting of three related plasma membrane proteins that play important roles in renal genesis and tubular cell proliferation: the membrane-bound precursor of the polypeptide growth factor EGF (preproEGF), which is expressed on apical surfaces of epithelial cells in the thick ascending limb of Henle (TALH) and distal convoluted tubule; the membrane-bound precursor of a structurally related polypeptide, transforming growth factor alpha (proTGFalpha), which appears to be expressed on apical membranes of collecting tubule cells; and the cellular receptor for EGF and TGFalpha (EGFR), which is found on basolateral surfaces of most renal tubule segments. Asymmetric localization of ligand and receptor may help explain why renal epithelial cells are normally quiescent in vivo except during tubular damage. PreproEGF, TGFalpha, and EGFR surface polarity may also influence kidney organogenesis, since their expression is tightly regulated during development. It has recently been shown that surface polarity of some membrane proteins is altered in certain pathophysiological conditions. There are reports, for example, that EGFR polarity is partially reversed in cystic epithelia from patients with autosomal dominant polycystic kidney disease (ADPKD). If true, then EGF/TGFalpha signalling could be profoundly influenced by asymmetric expression of other cellular components in ADPKD epithelial cells, depending on where EGFR is expressed. The specific aims of this proposal will delineate intracellular trafficking of newly synthesized preproEGF, proTGFalpha, and EGFR in renal tubular epithelial cells; identify intrinsic sorting signals for preproEGF, proTGFalpha and EGFR in renal tubular epithelial cells; and determine the effect of regulated posttranslational Ser/Thr phosphorylation on EGFR trafficking in renal tubular epithelial cells, with an emphasis on post-endocytotic sorting pathways.