Regulation of Transforming Growth Factors

描述（由申请人提供）：ErbB信号网络在发育和稳态中具有多种作用，其组分是导致癌症的失调的常见和重要靶点。该网络包括来自EGF和神经调节蛋白亚家族的多个多肽配体和同源和异源二聚化的四种相关受体酪氨酸激酶ErbB 1 -ErbB 4。EGF相关配体的一个子集激活ErbB 4以及EGF-R。为了研究ErbB信号网络及其组分之间的相互作用，我们系统地灭活了编码EGF家族配体的基因。在之前的资助期间，衍生小鼠的研究揭示了EGF样配体在发育和妊娠乳腺以及胃肠道中的独特和重要作用。最近，我们证明HB-EGF-/-幼崽出生后不久经常死亡，显示心脏瓣膜和肺发育缺陷，幸存者的心脏通常扩大。我们还发现，缺乏其他三种EGF家族配体的存活小鼠的HB-EGF的额外损失产生胚胎致死性。最后，分别缺乏TGF α、HB-EGF和最近发现的去整合素-金属蛋白酶TACE的小鼠的表型的相似性使我们提出TACE是TGF α和HB-EGF的生理转化酶，该提议随后得到生化证据的支持。我们现在建议扩展这些研究，解决有关EGF家族配体和ErbB网络的基本问题。我们的具体目标是：（1）鉴定四重缺失小鼠胚胎致死的潜在表型，并确定缺陷是否与EGF-R或ErbB 4的已知作用一致;（2）确定负责HB-EGF缺失的心脏和肺表型的机制;（3）检验HB-EGF与其他EGF家族配体相比具有独特作用的假设，以及其生理作用部分通过额外的ErbB受体介导的可能性;和（4）评估对HB-EGF的可溶性与膜锚定形式的需求。

DESCRIPTION (provided by applicant): The ErbB signaling network has multiple roles in development and homeostasis, and its components are frequent and important targets of deregulation leading to cancer. The network comprises multiple polypeptide ligands from the EGF and neuregulin subfamilies and four related receptor tyrosine kinases, ErbB 1 -ErbB4, that homo- and heterodimerize. A subset of EGF-related ligands activates ErbB4 as well as EGF-R. To investigate roles for the ErbB signaling network and interactions among its components we have systematically inactivated genes encoding EGF family ligands. During the previous funding period, studies of the derived mice revealed unique and important roles for EGF-like ligands in the developing and pregnant mammary gland, and in the gastrointestinal tract. Recently, we demonstrated that HB-EGF-/- pups frequently die shortly after birth, displaying defective cardiac heart valves and lung development, and hearts of survivors are often enlarged. We also discovered that additional loss of HB-EGF from viable mice lacking three other EGF family ligands produces embryonic lethality. Finally, similarities in the phenotypes of mice separately lacking TGFa, HB-EGF and the recently discovered disintegrin-metalloproteinase, TACE, led us to propose that TACE is a physiological convertase for both TGFa and HB-EGF, a proposal subsequently supported by biochemical evidence. We now propose to extend these studies, addressing fundamental issues regarding EGF family ligands and the ErbB network. Our specific aims are to: (1) identify phenotypes underlying the embryonic lethality of quadruple null mice, and determine if defects are consistent with known actions of EGF-R or ErbB4; (2) determine mechanisms responsible for the HB-EGF-null heart and lung phenotypes; (3) test the hypothesis that HB-EGF has unique actions compared to other EGF family ligands, as well as the possibility that its physiological actions are mediated in part through additional ErbB receptors; and (4) evaluate the requirement for soluble versus membrane-anchored forms of HB-EGF.