Positive and negative tissue-specific signaling by a nematode epidermal growth factor receptor
Positive and negative tissue-specific signaling by a nematode epidermal growth factor receptor
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DOI：
10.1091/mbc.8.5.779
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发表时间：
1997-05-01
影响因子：
3.3
通讯作者：
Sternberg, PW
中科院分区：
文献类型：
--
作者：
Lesa, GM;Sternberg, PW
受体酪氨酸激酶（RTK）信号传导特异性的主要决定因素是Src同源性2（SH 2）结合位点，即受体胞质结构域中含有磷酸酪氨酸的寡肽。秀丽隐杆线虫表皮生长因子受体同源物LET-23在发育过程中具有多种功能，并且在其激酶结构域的羧基末端区域具有8个潜在的SH 2结合位点。通过分析三种不同的LET-23功能的转基因线虫，我们发现，八个潜在的网站中有六个在体内发挥作用，它们是大多数，但不是全部，LET-23活性所需的。单个位点是促进野生型育性所必需的且足够的。另外三个位点激活RAS通路，并且仅涉及活力和外阴分化。第五个位点是混杂的，可以介导所有三种LET-23功能。一个额外的网站介导的组织特异性负调控。因此，假定的SH 2结合位点是完整生物体中细胞特异性和负调控的关键效应子。我们提出了两种不同的组织特异性RTK介导的信号传导机制。积极的机制将通过仅存在于某些细胞类型中的效应物促进RTK功能。负性机制通过组织特异性负性调节因子抑制RTK功能。
The major determinants of receptor tyrosine kinase (RTK) signaling specificity have been proposed to be Src homology 2 (SH2) binding sites, phosphotyrosine-containing oligopeptides in the cytoplasmic domain of the receptor. The Caenorhabditis elegans epidermal growth factor receptor homologue LET-23 has multiple functions during development and has eight potential SH2-binding sites in a region carboxyl terminal to its kinase domain. By analyzing transgenic nematodes for three distinct LET-23 functions, we show that six of eight potential sites function in vivo and that they are required for most, but not all, of LET-23 activity. A single site is necessary and sufficient to promote wild-type fertility. Three other sites activate the RAS pathway and are involved only in viability and vulval differentiation. A fifth site is promiscuous and can mediate all three LET-23 functions. An additional site mediates tissue-specific negative regulation. Putative SH2 binding sites are thus key effectors of both cell-specific and negative regulation in an intact organism. We suggest two distinct mechanisms for tissue-specific RTK-mediated signaling. A positive mechanism would promote RTK function through effectors present only in certain cell types. A negative mechanism would inhibit RTK function through tissue-specific negative regulators.