Integrin Signaling in Hemostasis and Blood Diseases

止血和血液疾病中的整合素信号传导

• 批准号: 8213654
• 负责人: SANFORD J SHATTIL
• 金额: $ 125.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213654
• 关键词: Actins; Adhesions; Adhesives; Administrative Coordination; Affect; Affinity; Area; Avidity; Basement membrane; Biological; Blood; Blood Cells; Blood Platelets; Blood Vessels; Cell Adhesion; Cell membrane; Cell physiology; Cell-Cell Adhesion; Cells; Cellular biology; Consensus; Cytoskeleton; Development; Differentiation and Growth; Disease; Edema; Endothelial Cells; Extracellular Matrix; Extracellular Matrix Proteins; F-Actin; Family; Gene Expression; Gene Targeting; Genes; Goals; Growth Factor Receptors; Growth and Development function; Hematological Disease; Hematopoietic; Hematopoietic stem cells; Hemostatic function; Homing; Hypoxia; Individual; Inflammation; Inflammatory; Injury; Integrin beta3; Integrins; Ischemia; Knowledge; Learning; Leukocytes; Libraries; Ligation; Lymphocyte; Lymphoid Tissue; Marrow; Mediating; Membrane Proteins; Mitogen-Activated Protein Kinase 3; Molecular; Mus; Myocardial Infarction; Outcome; Pathologic Processes; Platelet aggregation; Play; Process; Property; Protein Tyrosine Kinase; Proteins; Receptor Signaling; Recombinant Proteins; Recruitment Activity; Research; Research Personnel; Role; Semaphorin-3A; Signal Transduction; Site; Smooth Muscle Myocytes; Stimulus; Stromal Cells; Talin; Testing; Thrombosis; Thrombus; Time; Tissues; Tyrosine Phosphorylation; Vascular Endothelial Growth Factors; adhesion receptor; angiogenesis; base; cell growth; cell motility; cellular imaging; genetic regulatory protein; human DOK1 protein; member; migration; neutrophil; operation; programs; receptor; repaired; response; small hairpin RNA; src-Family Kinases

DESCRIPTION (provided by applicant): Cell-extracellular matrix interactions are tightly regulated by "inside-out" signals that activate integrins. Integrin ligation and clustering localize and activate proteins at cell adhesion sites to initiate "outside-in" signals that mediate biological responses. No where is this bidirectional signaling more apparent than in blood and vascular cells, where integrins control growth, differentiation, survival and function. The purpose of this Program Project is to characterize fundamental mechanisms of integrin signaling in blood and vascular cells. Individual projects will examine platelets, endothelial cells and smooth muscle cells, but the common goal is to identify general rules of integrin signaling. Project 1 will test the hypothesis that outside-in signaling in platelets is triggered by dynamic and direct interactions between integrins, Src family kinases and Src regulatory proteins. Molecular mechanisms of this process will be characterized, and consequences of disrupting these interactions on thrombus formation will be determined in gene-targeted mice. Project 2 has characterized the roles of ERK 1/2, Rap1, R-Ras and PEA-15 in integrin activation. It will now test the hypothesis that specific effectors of Rap1 and R-Ras mediate this process, in part through interactions with talin. Since PEA-15 is expressed in vascular cells, its roles in vessel repair and angiogenesis will be determined. Project 3 will characterize how integrin ligation influences endothelial cell barrier disruption induced by VEGF during ischemic disease and how basement membrane proteins exposed during vascular leak recruit platelets to form deleterious micro-thrombi. It will also characterize how semaphorin-3A promotes vascular leak in the absence of VEGF and inhibits angiogenesis. Project 4 will examine relationships between the Abl tyrosine kinase and integrin signaling. It will test the hypotheses that beta3 integrin activates Abl through Src-dependent tyrosine phosphorylation of p62Dok-1, and that Abl phosphorylates Src-substrates to inhibit cell spreading. The relationships between Abl and known regulators of F-actin will be determined by identification of genes that modulate Abl function using an shRNA library screen. These projects will be supported by core units that provide recombinant proteins, cell imaging capabilities and administrative coordination. The synergy achieved by this Program will further our understanding of integrin signaling, with implications for disorders of cell adhesion affecting hemostasis and vascular repair.

描述（由申请人提供）： 细胞与细胞外基质的相互作用受到激活整合素的“由内而外”信号的严格调节。 整合素连接和聚集定位并激活细胞粘附位点的蛋白质，以启动“由外向内” 传递生物反应的信号。这种双向信号传导在血液和血管细胞中最为明显，在这些细胞中整合素控制着生长、分化、存活和功能。该项目的目的是描述整合素在血液和血管细胞中的信号传导的基本机制。个别项目将检查血小板，内皮细胞和平滑肌细胞，但共同的目标是确定整合素信号转导的一般规则。项目1将检验血小板中由外向内信号传导是由整合素、Src家族激酶和Src调节蛋白之间的动态和直接相互作用触发的假设。这一过程的分子机制将被表征，并且将在基因靶向小鼠中确定破坏这些相互作用对血栓形成的后果。项目2已经表征了ERK 1/2、Rap 1、R-Ras和PEA-15在整合素活化中的作用。现在将测试Rap 1和R-Ras的特定效应物介导这一过程的假设，部分通过与talin的相互作用。由于PEA-15在血管细胞中表达，因此将确定其在血管修复和血管生成中的作用。项目3将描述整合素连接如何影响缺血性疾病期间VEGF诱导的内皮细胞屏障破坏，以及血管渗漏期间暴露的基底膜蛋白如何招募血小板形成有害的微血栓。它还将表征semaphorin-3A如何在缺乏VEGF的情况下促进血管渗漏并抑制血管生成。项目4将研究Abl酪氨酸激酶和整合素信号之间的关系。它将测试β 3整联蛋白通过p62 Dok-1的Src依赖性酪氨酸磷酸化激活Abl以及Abl磷酸化Src底物以抑制细胞扩散的假设。Abl和已知的F-肌动蛋白调节因子之间的关系将通过使用shRNA文库筛选鉴定调节Abl功能的基因来确定。这些项目将得到提供重组蛋白、细胞成像能力和行政协调的核心单位的支持。该项目所实现的协同作用将进一步加深我们对整合素信号传导的理解，并对影响止血和血管修复的细胞粘附障碍产生影响。

项目成果

Coordinate interactions of Csk, Src, and Syk kinases with [alpha]IIb[beta]3 initiate integrin signaling to the cytoskeleton.

• DOI: 10.1083/jcb.200112113
• 发表时间: 2002-04-15
• 期刊: The Journal of cell biology
• 作者: Obergfell A;Eto K;Mocsai A;Buensuceso C;Moores SL;Brugge JS;Lowell CA;Shattil SJ
• 通讯作者: Shattil SJ

MicroRNA regulation of endothelial TREX1 reprograms the tumour microenvironment.

• DOI: 10.1038/ncomms13597
• 发表时间: 2016-11-25
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Wilson, RaeAnna;Espinosa-Diez, Cristina;Kanner, Nathan;Chatterjee, Namita;Ruhl, Rebecca;Hipfinger, Christina;Advani, Sunil J.;Li, Jie;Khan, Omar F.;Franovic, Aleksandra;Weis, Sara M.;Kumar, Sushil;Coussens, Lisa M.;Anderson, Daniel G.;Chen, Clark C.;Cheresh, David A.;Anand, Sudarshan
• 通讯作者: Anand, Sudarshan

Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption.

• DOI: 10.1083/jcb.200611083
• 发表时间: 2007-03-12
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Zou, Wei;Kitaura, Hideki;Reeve, Jennifer;Long, Fanxin;Tybulewicz, Victor L J;Shattil, Sanford J;Ginsberg, Mark H;Ross, F Patrick;Teitelbaum, Steven L
• 通讯作者: Teitelbaum, Steven L

Effects of cell tension on the small GTPase Rac.

• DOI: 10.1083/jcb.200201105
• 发表时间: 2002-07-08
• 期刊: The Journal of cell biology
• 作者: Katsumi A;Milanini J;Kiosses WB;del Pozo MA;Kaunas R;Chien S;Hahn KM;Schwartz MA
• 通讯作者: Schwartz MA

Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration.

• DOI: 10.1038/ncb1868
• 发表时间: 2009-05
• 期刊: NATURE CELL BIOLOGY
• 影响因子: 21.3
• 作者: Huang, Cai;Rajfur, Zenon;Yousefi, Nima;Chen, Zaozao;Jacobson, Ken;Ginsberg, Mark H.
• 通讯作者: Ginsberg, Mark H.