Establishing Function of Understudied PRKCQ Kinase in Cellular Regulation and Disease

摘要/摘要 我们研究的总体愿景是全面了解 驱动未被充分研究的激酶PRKCQ功能的分子机制 把它作为疾病的靶子。PRKCQ编码蛋白激酶C(PKC)同工酶PKCq。PKC家族 自20世纪80年代初发现以来，人们在癌症的背景下进行了密集的研究 它是促进肿瘤的佛波酯的受体。这导致了一种教条，即激活 佛波酯对PKC的作用促进致癌物诱导的肿瘤发生。尽管如此，PKC已经 尽管进行了几十年的研究，但仍是一个难以捉摸的化疗靶点。我们最近建立了 与传统的想法相反，PKC通常作为肿瘤抑制因子发挥作用，而不是 致癌基因，从而解释了为什么30多年来PKC抑制剂的临床试验不仅失败了，而且， 在某些情况下，这会恶化患者的预后。在这项提案中，我们的目标是结合生物信息学， 快速理解分子细节的计算、生物化学和细胞方法 以及疾病相关突变如何影响功能和生物学。揭开 PKCq在致癌信号转导中的作用将提示如何在癌症中适当地靶向它 治疗。

Summary/Abstract The overall vision of our research is to gain a comprehensive understanding of the molecular mechanisms driving the function of understudied kinase PRKCQ in order to effectively target it in disease. PRKCQ encodes the protein kinase C (PKC) isozyme PKCq. The PKC family has been intensely investigated in the context of cancer since the discovery in the early 1980s that it is a receptor for the tumor-promoting phorbol esters. This led to the dogma that activation of PKC by phorbol esters promotes carcinogen-induced tumorigenesis. Nonetheless, PKC has been an elusive chemotherapeutic target despite decades of research. We recently established that, contrary to conventional thinking, PKC generally functions as a tumor suppressor, not an oncogene, thus explaining why 30+ years of clinical trials with PKC inhibitors not only failed but, in some cases, worsened patient outcome. In this proposal, we aim to combine bioinformatics, computational, biochemical, and cellular approaches to rapidly understand the molecular details of PKCq and how disease-associated mutations impact function and biology. Uncovering the function of PKCq in oncogenic signaling will inform on how to appropriately target it in cancer therapies.