Signal Transduction Pathways in Melanoma

描述(由申请人提供)：本提案的目标是了解MKK/ERK和Rho GTPase通路之间的信号整合如何控制黑色素瘤的进展。初步研究提供了新的证据，表明在黑色素瘤中，RAC和Rho GTP酶以及MKK/ERK以一种阶段特异性的方式被激活。活性Rac在早期而不是晚期促进转化，活性RhoA在晚期但不是早期促进侵袭。RAC/Rho和MKK/ERK信号通路之间的一个重要联系是由MKK/ERK抑制丛蛋白B1和SEMA 3C的新发现提供的，这为MKK/ERK和丛/信号素通路之间的交叉调节提供了新的证据。Plexin B1在早期细胞中具有新的肿瘤抑制作用，而在晚期细胞中则抑制迁移和侵袭。SemaSC部分地分享了这一功能，作为移民和入侵的抑制者。第二个关联涉及RhoA依赖的蛋白的诱导，我们称之为Rho依赖的侵袭介体(MRDI)，它是肌动蛋白应激纤维和焦点黏附事件的新调节因子，与RhoA合作促进转移细胞的侵袭。具体目标1将研究MRDI及其促进Rho依赖的细胞侵袭的机制。特殊目标2将研究丛状蛋白B1及其被MKK/ERK抑制如何控制黑色素瘤的肿瘤形成和侵袭。具体目标3将研究MKK/ERK和RAC之间的组合相互作用，这可能促进转化。具体目标4将研究Sema3C-它对黑色素瘤的重要性以及MKK/ERK抑制它的机制。我们的数据显示，黑色素瘤是一个独特的模型，可以了解MKK/ERK、RAC和Rho通路如何相互作用促进肿瘤的生长和侵袭，以及对信号机制的反应如何随着癌症分期的不同而变化。这些研究将结合蛋白质组学的创新方法与分子生物学、生物化学和细胞生物学来揭示这种疾病的新机制。

DESCRIPTION (provided by applicant): The goal of this proposal is to understand how integration of signaling between MKK/ERK and Rho GTPase pathways controls melanoma progression. Preliminary studies provide novel evidence that in melanoma, Rac and Rho GTPases, along with MKK/ERK, are activated in a stage-specific manner. Active Rac promotes transformation in early but not late stages, and active RhoA promotes invasion in late, but not early stages. An important link between Rac/Rho and MKK/ERK signaling is provided by new findings that plexin B1 and sema 3C are repressed by MKK/ERK, providing novel evidence for crossregulation between MKK/ERK and plexin/semaphorin pathways. Plexin B1 has a novel tumor suppressor role in early stage cells, while suppressing migration and invasion in late stage cells. SemaSC partly shares this function, as a suppressor of migration and invasion. A second link involves RhoA-dependent induction of a protein we have named Mediator of Rho-dependent Invasion (MRDI), a novel regulator of actin stress fibers and focal adhesion events which collaborates with RhoA to promote metastatic cell invasion. Specific Aim 1 will investigate MRDI and the mechanism by which it promotes Rho-dependent cell invasion. Specific Aim 2 will examine plexin B1 and how its repression by MKK/ERK controls tumor formation and invasion in melanoma. Specific Aim 3 will investigate combinatorial interactions between MKK/ERK and Rac which may promote transformation. Specific Aim 4 will investigate sema3C-its importance for melanoma and the mechanisms involved in its repression by MKK/ERK. Our data show that melanoma is a unique model for understanding how MKK/ERK, Rac, and Rho pathways interact to promote tumor growth and invasion, and how responses to signaling mechanisms vary with cancer stages. These studies will combine innovative approaches of proteomics profiling with molecular biology, biochemistry, and cell biology to uncover novel mechanisms underlying this disease.