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Plexin signalling in melanocyte biology and melanoma progression

黑色素细胞生物学和黑色素瘤进展中的 Plexin 信号传导

基本信息

批准号：
8505397
负责人：
GLYNIS A SCOTT
金额：
$ 29.23万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8505397
关键词：
Adhesions Benign Biology CD100 antigen Cell Line Cell Survival Cell physiology Cell-Cell Adhesion Cells Coculture Techniques Cutaneous Melanoma Data Dendrites Disease Down-Regulation Epidermis Equilibrium Fibroblasts Formalin GTP-Binding Proteins Goals Growth Growth Factor Hepatocyte Growth Factor Homeostasis Human Immigration Integrins LIM Domain Kinase 1 Ligands Mediating Melanins Melanoma Cell Metastatic Melanoma Minority Modeling Neoplasm Metastasis Nervous system structure Neural Crest Neurites Neuropilins Nevi and Melanomas Organogenesis Paraffin Embedding Pathway interactions Patients Pigmentation Disorders Pigmentation physiologic function Population Process Production Protein Family Proteins Publishing Receptor Activation Receptor Down-Regulation Receptor Inhibition Receptor Signaling Regulation Relative (related person)Reporting Role Sampling Semaphorins Signal Pathway Signal Transduction Skin Skin Cancer Skin Pigmentation Stem cells Testing Tissue Microarray Tumor Suppressor Proteins Ultraviolet B Radiation Ultraviolet Rays axon guidance cell growth cell motility cell type cofilin immune function immunoregulation in vivo keratinocyte meetings melanocyte melanoma migration minimally invasive new growth novel paracrine photoprotection plexin public health relevance receptor receptor expression response rho tumor progression

项目摘要

DESCRIPTION (provided by applicant): Human melanocytes are neural crest derived cells that perform a unique function in the skin. While they are a minority of the population of the epidermis, they are responsible for the majority of photoprotection of the skin from ultraviolet radiation (UVR) through the production and transfer of melanin to keratinocytes [1]. Melanocytes, or their stem cells, are also progenitor cells for the most deadly of skin cancers, melanoma, which arises as a step wise progression from benign, to minimally invasive, to metastatic tumor [2]. Paracrine factors, produced primarily by keratinocytes, but also by fibroblasts, control multiple melanocyte functions, including dendricity, migration, growth and pigmentation, and also regulate normal homeostasis of melanocytes in the skin. Disordered of these growth factors, their receptors, or signaling pathways, are implicated in melanoma progression, as well as in disordered pigmentation [3]. Therefore, discovery of new or novel paracrine factors, and defining receptors and signaling pathways stimulated by these factors, are important to understanding melanocyte regulation in the skin, and melanoma tumor progression. Semaphorins are a large family of proteins that were originally identified in the nervous system, and are critical regulators of axon guidance. During the last 5 years, numerous reports show that semaphorins and their receptors (Plexins and Neuropilins) are widely distributed and regulate multiple biologic processes, including cell adhesion and migration, neurite extension, immune function, organogenesis, and tumor progression. Our published and preliminary data show a previously unrecognized role for semaphorins in human melanocyte function. Semaphorin 4D and semaphorin 7A regulate multiple cellular processes in other cell types, including neurite outgrowth and retraction, tumor progression and immune modulation [4]. We are the first to show that semaphorin 4D (Sema4D) and semaphorin 7A (Sema7A) control melanocyte attachment, spreading and dendricity, which are critically important for normal skin pigmentation. Further, our data suggest a potential role for Sema4D and Sema7A in melanoma progression, because their cognate receptors (Plexin B1 and Plexin C1 respectively) are either reduced or absent in melanoma. Finally, our preliminary data indicate a novel role for Sema4D in downregulation of c-Met receptor activation, a receptor critically important for melanocyte cell growth, migration, differentiation, and melanoma progression. We hypothesize that Sema4D and Sema7A regulate melanocyte migration and dendrite formation through stimulation of intracellular signaling pathways that include the GTP binding proteins Ras, Rho, Rac, integrins and LIM kinase- cofilin pathways. We predict that effects of Sema7A are mediated by a balance between 1- integrin and cofilin activation. We predict that effects of Sema4D are mediated by a balance between c-Met receptor inhibition and Plexin B1 activation. Finally, we predict that loss of Plexin B1 and Plexin C1 expression contribute to melanoma progression through enhanced melanoma cell growth, migration, and survival due to loss of c-Met receptor inhibition and coflin activation, respectively.

描述（由申请人提供）：人类黑素细胞是神经嵴衍生的细胞，在皮肤中发挥独特的功能。虽然它们在表皮中占少数，但它们通过产生黑色素并将其转移到角质形成细胞[1]，承担了皮肤免受紫外线辐射（UVR）的大部分光保护作用。黑素细胞或它们的干细胞，也是最致命的皮肤癌黑色素瘤的祖细胞，黑色素瘤是一个从良性到微创再到转移性肿瘤的渐进过程。旁分泌因子主要由角质形成细胞产生，也由成纤维细胞产生，控制多种黑素细胞的功能，包括树突、迁移、生长和色素沉着，并调节皮肤中黑素细胞的正常稳态。这些生长因子、其受体或信号通路的紊乱与黑色素瘤的进展以及色素沉着紊乱有关。因此，发现新的或新的旁分泌因子，定义受这些因子刺激的受体和信号通路，对于理解皮肤中的黑素细胞调节和黑色素瘤肿瘤进展非常重要。信号蛋白是最初在神经系统中发现的一个大家族蛋白，是轴突引导的关键调节因子。在过去的5年中，大量报道表明信号蛋白及其受体（丛蛋白和神经肽）广泛分布并调节多种生物过程，包括细胞粘附和迁移、神经突延伸、免疫功能、器官发生和肿瘤进展。我们发表的和初步的数据显示了信号素在人类黑素细胞功能中以前未被认识到的作用。信号蛋白4D和信号蛋白7A调节其他细胞类型的多种细胞过程，包括神经突的生长和收缩、肿瘤的进展和免疫调节[4]。我们首次发现信号蛋白4D （Sema4D）和信号蛋白7A （Sema7A）控制黑素细胞的附着、扩散和树突，这对正常的皮肤色素沉着至关重要。此外，我们的数据表明Sema4D和Sema7A在黑色素瘤进展中的潜在作用，因为它们的同源受体（分别为Plexin B1和Plexin C1）在黑色素瘤中减少或缺失。最后，我们的初步数据表明Sema4D在下调c-Met受体激活中的新作用，c-Met受体对黑素细胞的生长、迁移、分化和黑色素瘤的进展至关重要。我们假设Sema4D和Sema7A通过刺激细胞内信号通路，包括GTP结合蛋白Ras、Rho、Rac、整合素和LIM激酶- cofilin通路，调节黑素细胞迁移和树突形成。我们预测Sema7A的作用是由1-整合素和cofilin激活之间的平衡介导的。我们预测Sema4D的作用是由c-Met受体抑制和丛蛋白B1激活之间的平衡介导的。最后，我们预测，由于c-Met受体抑制和coflin激活的丧失，Plexin B1和Plexin C1表达的丧失分别通过增强黑色素瘤细胞的生长、迁移和存活，促进了黑色素瘤的进展。