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

• 批准号: 8291374
• 负责人: GLYNIS A SCOTT
• 金额: $ 31.1万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291374
• 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

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. PUBLIC HEALTH RELEVANCE. Identification of new growth factors that regulate human melanocyte function is important for understanding pigmentation of the skin, and in the transformation of benign melanocytes to malignant melanoma. We have identified two proteins, Semaphorin 4D and Semaphorin 7A, which stimulate human melanocyte function through the receptors Plexin B1 and Plexin C1 respectively. Further, we show that both of these receptors are reduced or absent in melanoma cell lines, and, in the case of Plexin C1, in melanoma in vivo. The goal of this project is to define how Semaphorins signal through Plexin receptors, and to understand the mechanisms by which loss of Plexin receptor expression contributes to melanoma metastasis.

描述（由申请人提供）：人类黑素细胞是神经嵴衍生的细胞，在皮肤中执行独特的功能。虽然它们只占表皮群体的一小部分，但它们通过产生黑色素并将其转移至角质形成细胞，负责皮肤免受紫外线辐射 (UVR) 的大部分光保护 [1]。黑色素细胞或其干细胞也是最致命的皮肤癌黑色素瘤的祖细胞，黑色素瘤是从良性肿瘤到微创肿瘤再到转移性肿瘤的逐步进展而产生的[2]。旁分泌因子主要由角质形成细胞产生，但也由成纤维细胞产生，控制多种黑色素细胞功能，包括树突、迁移、生长和色素沉着，还调节皮肤中黑色素细胞的正常稳态。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[3]。因此，发现新的或新颖的旁分泌因子，并定义这些因子刺激的受体和信号通路，对于了解皮肤中黑素细胞的调节和黑色素瘤的进展非常重要。信号蛋白是一个大家族的蛋白质，最初是在神经系统中发现的，是轴突引导的关键调节因子。在过去的5年中，大量报告表明，信号蛋白及其受体（Plexins和Neuropilins）分布广泛，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。我们发表的初步数据显示了信号蛋白在人类黑素细胞功能中的先前未被认识到的作用。 Semaphorin 4D 和 semaphorin 7A 调节其他细胞类型的多种细胞过程，包括神经突生长和回缩、肿瘤进展和免疫调节 [4]。我们首次证明脑信号蛋白 4D (Sema4D) 和脑信号蛋白 7A (Sema7A) 控制黑素细胞附着、扩散和树突，这对于正常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 受体激活对黑色素细胞的生长、迁移、分化和黑色素瘤进展至关重要。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、整联蛋白和 LIM 激酶-丝切蛋白通路）来调节黑素细胞迁移和树突形成。我们预测 Sema7A 的作用是由 1-整合素和丝切蛋白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 Plexin B1 激活之间的平衡介导的。最后，我们预测 Plexin B1 和 Plexin C1 表达的丧失分别由于 c-Met 受体抑制和 coflin 激活的丧失，通过增强黑色素瘤细胞的生长、迁移和存活，从而导致黑色素瘤进展。 公共卫生相关性。识别调节人类黑色素细胞功能的新生长因子对于了解皮肤色素沉着以及良性黑色素细胞向恶性黑色素瘤的转化非常重要。我们已经鉴定出两种蛋白质：Semaphorin 4D 和 Semaphorin 7A，它们分别通过受体 Plexin B1 和 Plexin C1 刺激人类黑素细胞功能。此外，我们还发现，这两种受体在黑色素瘤细胞系中均减少或缺失，对于 Plexin C1，在体内黑色素瘤中也是如此。该项目的目标是确定信号蛋白如何通过 Plexin 受体发出信号，并了解 Plexin 受体表达缺失导致黑色素瘤转移的机制。