Regulation of Transforming Growth Factors

描述(由申请人提供)：ErbB信号网络在发育和动态平衡中具有多种作用，其组件是导致癌症的放松管制的常见和重要靶点。该网络包括来自EGF和neuRegin亚家族的多个多肽配体和四个相关的受体酪氨酸激酶ErbB1-ErbB4，它们是同源和异源二聚体。EGF相关配体的子集可以激活ErbB4和EGF-R。为了研究ErbB信号网络的作用及其组件之间的相互作用，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，对衍生小鼠的研究表明，EGF样配体在发育和怀孕的乳腺以及胃肠道中发挥着独特而重要的作用。最近，我们证明了HB-EGF-/-幼鼠经常在出生后不久死亡，表现为心脏瓣膜和肺发育缺陷，幸存者的心脏通常增大。我们还发现，缺乏其他三种EGF家族配体的存活小鼠的HB-EGF额外丢失会导致胚胎死亡。最后，分别缺乏TGFa和HB-EGF的小鼠的表型与最近发现的去整合素-金属蛋白酶TACE的表型相似，这导致我们提出TACE是TGFa和HB-EGF的生理转换酶，这一假设随后得到了生化证据的支持。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)鉴定导致四缺失小鼠胚胎致死的表型，并确定缺陷是否与EGF-R或ErbB4的已知作用一致；(2)确定HB-EGF缺失的心脏和肺表型的责任机制；(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；以及(4)评估可溶性与膜锚定形式的HB-EGF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.