Basolateral EGF receptor sorting regulated by functionally distinct mechanisms in renal epithelial cells.
Basolateral EGF receptor sorting regulated by functionally distinct mechanisms in renal epithelial cells.
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DOI：
10.1111/tra.12032
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Carlin CR
中科院分区：
文献类型：
--
作者：
Cotton CU;Hobert ME;Ryan S;Carlin CR
上皮组织的增殖受包括EGF受体（EGFR）在内的信号受体的极化分布控制。在肾脏中，EGFR通过选择性靶向基底外侧膜而与肾单位顶液中存在的可溶性配体分离。我们先前已经表明，上皮特异性网格蛋白衔接子AP 1B介导已建立的上皮细胞中的基底外侧EGFR分选。在这里，我们表明，蛋白激酶C（PKC）依赖性磷酸化的Thr 654调节表皮生长因子受体的极性上皮细胞形成新的细胞-细胞连接复合物。在极化细胞中，AP 1B依赖性通路不覆盖PKC耐药T654 A突变，相反，AP 1B缺陷型EGFR通过PKC依赖性机制进行基底侧排序。令人惊讶的是，干扰这些不同分选途径的EGFR突变也在三维器官型培养物中产生非常不同的表型。因此，EGFR根据基底外侧分选途径执行不同的功能。许多肾脏疾病有缺陷的细胞极性和概念，顶端错误定位的EGFR促进增殖仍然是一个有吸引力的模型来解释多囊肾病的许多方面。我们的数据表明，EGFR还通过在发育中的上皮细胞中在不同BL分选程序之间切换来整合极性的各个方面。因此，对EGFR分选的基本机制的基础知识为这些肾脏疾病的发病机制和药物发现提供了新的见解。
Proliferation of epithelial tissues is controlled by polarized distribution of signaling receptors including the EGF receptor (EGFR). In kidney, EGFRs are segregated from soluble ligands present in apical fluid of nephrons by selective targeting to basolateral membranes. We have shown previously that the epithelial-specific clathrin adaptor AP1B mediates basolateral EGFR sorting in established epithelia. Here we show that protein kinase C (PKC)-dependent phosphorylation of Thr654 regulates EGFR polarity as epithelial cells form new cell-cell junctional complexes. The AP1B-dependent pathway does not override a PKC-resistant T654A mutation, and conversely AP1B-defective EGFRs sort basolaterally by a PKC-dependent mechanism, in polarizing cells. Surprisingly, EGFR mutations that interfere with these different sorting pathways also produce very distinct phenotypes in three-dimensional organotypic cultures. Thus EGFRs execute different functions depending on the basolateral sorting route. Many renal disorders have defects in cell polarity and the notion that apically mislocalized EGFRs promote proliferation is still an attractive model to explain many aspects of polycystic kidney disease. Our data suggest EGFR also integrates various aspects of polarity by switching between different BL sorting programs in developing epithelial cells. Fundamental knowledge of basic mechanisms governing EGFR sorting therefore provides new insights into pathogenesis and advances drug discovery for these renal disorders.
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影响因子：
64.5
作者：
Fölsch, H;Ohno, H;Mellman, I
通讯作者：
Mellman, I
影响因子：
3.3
作者：
Doray, Balraj;Lee, Intaek;Kornfeld, Stuart
通讯作者：
Kornfeld, Stuart
DOI：
10.1083/jcb.200408165
发表时间：
2004-11-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ang AL;Taguchi T;Francis S;Fölsch H;Murrells LJ;Pypaert M;Warren G;Mellman I
通讯作者：
Mellman I
影响因子：
11.8
作者：
Gray, Ryan S.;Roszko, Isabelle;Solnica-Krezel, Lilianna
通讯作者：
Solnica-Krezel, Lilianna
DOI：
10.1073/pnas.82.12.4080
发表时间：
1985-01-01
影响因子：
11.1
作者：
DAVIS, RJ;CZECH, MP
通讯作者：
CZECH, MP