Signal Transduction Pathways in Melanoma

描述（由申请方提供）：本提案的目的是了解MKK/ERK和Rho GT3通路之间的信号整合如何控制黑色素瘤进展。初步研究提供了新的证据表明，在黑色素瘤中，Rac和Rho GTP酶，沿着MKK/ERK，以阶段特异性方式被激活。活性Rac促进早期而非晚期的转化，活性RhoA促进晚期而非早期的侵袭。新的研究发现丛蛋白B1和sema 3C被MKK/ERK抑制，这为MKK/ERK和丛蛋白/脑信号蛋白通路之间的交叉调节提供了新的证据。丛蛋白B1在早期细胞中具有新的肿瘤抑制作用，同时抑制晚期细胞的迁移和侵袭。SemaSC部分地分享这一功能，作为迁移和入侵的抑制剂。第二个联系涉及RhoA依赖性诱导的蛋白质，我们命名为Rho依赖性侵袭介导剂（MRDI），一种新型的肌动蛋白应力纤维和粘着斑事件的调节剂，与RhoA合作，促进转移性细胞侵袭。具体目标1将调查MRDI和它促进Rho依赖性细胞侵袭的机制。具体目标2将检查丛蛋白B1和如何通过MKK/ERK抑制控制黑色素瘤的肿瘤形成和侵袭。具体目标3将研究可能促进转化的MKK/ERK和Rac之间的组合相互作用。具体目标4将研究sema 3C-其对黑色素瘤的重要性及其通过MKK/ERK抑制的机制。我们的数据表明，黑色素瘤是一种独特的模型，用于了解MKK/ERK，Rac和Rho通路如何相互作用以促进肿瘤生长和侵袭，以及对信号传导机制的反应如何随癌症阶段而变化。这些研究将结合联合收割机蛋白质组学分析与分子生物学，生物化学和细胞生物学的创新方法，以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.