Cellular and Developmental Function of Mena

Mena 的细胞和发育功能

• 批准号: 7992376
• 负责人: FRANK B GERTLER
• 金额: $ 36.35万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992376
• 关键词: Actins; Adhesions; Affect; Animals; Attenuated; Award; Behavior; Binding; Biological Assay; Biology; Bundling; Cell Adhesion; Cells; Cellular biology; Chemotaxis; Cleft Palate; Congenital Abnormality; Cues; Defect; Development; Disease; EGF gene; Embryo; Endothelial Cells; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Epithelial Physiology; Epithelium; Event; Exhibits; Eye; Eyelid structure; F-Actin; Family; Fibroblasts; Filament; Funding; Genetic; Goals; In Vitro; Knockout Mice; Lead; Ligands; Malignant Epithelial Cell; Malignant Neoplasms; Membrane; Microfilaments; Molecular; Morphogenesis; Morphology; Movement; Mus; Neoplasm Metastasis; Neural tube; Neurons; Null Lymphocytes; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Positioning Attribute; Pregnancy; Process; Progress Reports; Protein Conformation; Protein Family; Protein Isoforms; Proteins; Publishing; RNA Splicing; Receptor Signaling; Refractory; Research; Role; Second Messenger Systems; Secondary Palate; Shapes; Signal Pathway; Signal Transduction; Skin; System; Testing; Tissues; Tumor Cell Invasion; Variant; Wound Healing; adhesion process; base; cancer cell; cell motility; driving force; genetic regulatory protein; in vivo; inhibitor/antagonist; insight; keratinocyte; member; migration; mutant; neoplastic cell; novel; polymerization; public health relevance; repaired; research study; response; second messenger; therapy resistant; vasodilator-stimulated phosphoprotein; wound

DESCRIPTION (provided by applicant): Understanding how a cell moves in response to environmental signals is a fundamental challenge in biology. Mena, VASP and EVL, highly related proteins that comprise the Ena/VASP family, play pivotal roles in movement and shape change1 for a variety of cells, including fibroblasts, endothelial cells, epithelial cells, and neurons; Ena/VASP directly regulates actin filament network assembly, modulate morphology and behavior of membrane protrusions, and influences cell motility. One major goal for the current proposal is to study how Ena/VASP function contributes to chemotactic responses in carcinoma cells. Chemotactic cues trigger second messenger pathways that activate kinases, and phosphorylate Ena/VASP proteins. Specific Mena isoforms play key roles in tumor cell invasion and motility in response to Epidermal Growth Factor Receptor (EGFR) signaling. Thus, we propose that Ena/VASP proteins integrate signals from second messenger pathways to execute required motile responses, and are thus not only well positioned to control chemotactic motility, but are in fact generally involved in systems that require guided motility. The study of Mena tumor invasion-specific isoforms is particularly relevant to understanding how tumor cells acquire the ability to move and respond to a chemotactic cue. A second major goal for the current proposal is to examine the requirements for Ena/VASP function in epidermal morphogenesis and wound repair using newly generated conditional knockout mice. Several lines of evidence indicate that Ena/VASP function is required for epithelial morphogenesis and epithelial sheet fusion. Throughout development, there are many morphogenetic episodes involving fusion of two epithelial sheets or shelves of tissue. The most fully explored of these events are fusion and zippering closed of the neural tube, of the two secondary palates, and of the eyelids as the eyes close part way through gestation; embryos deficient in Ena/VASP exhibit all of these defects. While the forces driving these tissues together have been partially described, very little is known about the genetics or cell biology of the final fusion events for any of these processes; if this final knitting together event fails, the consequences can be devastating, resulting in congenital abnormalities as severe as cleft palate or spina bifda. Epithelial sheet migration and fusion is also required during wound repair, another process we will examine in this proposal. Together, these studies will provide valuable insight into the mechanisms controlling cell motility in both normal development and disease. PUBLIC HEALTH RELEVANCE: Drugs that block the EGFR pathway are widely used to treat a variety of cancers; thus, by understanding how invasion-specific Mena isoforms sensitizes carcinoma cells to EGF and amplifies their response, valuable insight into how certain cancers become resistant to therapies that attenuate EGFR signaling will be gained. Epithelial sheet movements during process such as eyelid closure and wound healing are dependent of EGF and EGF-related factors, thus studies of Ena/VASP in epithelial migration and sheet fusion should prove valuable in developing new ways to enhance treatment of wounds.

描述（由申请人提供）：了解细胞如何响应环境信号是生物学的基本挑战。 MENA，VASP和EVL，包括ENA/VASP家族的高度相关蛋白质，在运动和形状变化中起关键作用1，用于各种细胞，包括成纤维细胞，内皮细胞，上皮细胞，上皮细胞和神经元； ENA/VASP直接调节肌动蛋白细丝网络组装，调节膜突起的形态和行为，并影响细胞运动。当前建议的主要目标是研究ENA/VASP功能如何有助于癌细胞的趋化反应。趋化提示触发激活激酶并磷酸化ENA/VASP蛋白的第二通路途径。特定的MENA同工型在响应表皮生长因子受体（EGFR）信号传导的肿瘤细胞侵袭中起关键作用。因此，我们提出ENA/VASP蛋白会整合来自第二通信途径的信号以执行所需的运动响应，因此不仅可以很好地控制趋化性运动性，而且实际上通常参与需要引导运动的系统。对MENA肿瘤浸润特异性同工型的研究特别与了解肿瘤细胞如何获得运动能力和对趋化性提示的能力有关。当前建议的第二个主要目标是检查使用新生成的条件基因敲除小鼠在表皮形态发生和伤口修复中对ENA/VASP功能的要求。几条证据表明，上皮形态发生和上皮板融合需要ENA/VASP功能。在整个发育过程中，都有许多形态发生发作，涉及两个上皮床单或组织架子的融合。这些事件中最充分的探索是融合和拉链封闭的神经管，两个次要口感和眼睑的封闭，因为眼睛通过妊娠一部分闭合。缺乏ENA/VASP的胚胎表现出所有这些缺陷。尽管部分描述了驱动这些组织的力量，但对于任何这些过程的最终融合事件的遗传学或细胞生物学知之甚少。如果最终的编织事件失败了，后果可能是毁灭性的，导致先天性异常严重，如cle裂或脊柱bifda。在伤口修复期间，还需要上皮片迁移和融合，这是我们将在此提案中检查的另一个过程。总之，这些研究将为控制正常发育和疾病中细胞运动的机制提供宝贵的见解。 公共卫生相关性：阻止EGFR途径的药物被广泛用于治疗各种癌症；因此，通过了解侵袭特异性的MENA同工型如何使癌细胞对EGF敏感并扩大其反应，从而有价值的洞察力对某些癌症如何对减轻EGFR信号的疗法具有抵抗力。在过程中，例如眼睑闭合和伤口愈合等过程中的上皮运动取决于EGF和与EGF相关的因素，因此在上皮迁移和床单融合中对ENA/VASP的研究应在开发新的方法来增强伤口治疗方面有价值。