Novel upstream regulatory and down-stream signaling mechanisms of the Src-family protein kinases

正常细胞的生长和分裂是由两组酶的平衡作用控制的——由原癌基因（致癌基因的前体）和肿瘤抑制基因编码的酶。这些酶的调节异常会导致癌症。事实上，一组被称为src家族激酶（SFKs）的原致癌酶的过度刺激是导致大多数人类癌症的主要因素。在这个应用中，我们提出研究sfk被其天然抑制剂CHK失活是如何抑制癌症形成的，以及sfk过度刺激是如何导致癌症的。CHK究竟是如何使sfk失活的仍不清楚。最近，我们发现了CHK抑制SFKs的一种新机制。在这种机制中，CHK与SFK紧密结合，仅结合就足以完全关闭SFK的活性。由于CHK的这种新的抑制机制可以用于开发用于癌症治疗的合成SFK抑制剂，我们提出揭示CHK如何与SFK紧密结合以及这种结合如何抑制SFK的促癌活性。过度刺激SFKs如何诱导人类癌症的发展一直是癌症研究中一个重要的突出问题。最近，我们和德克萨斯州的两组研究人员在回答这个问题上取得了突破。德克萨斯大学的研究小组发现，过度刺激的sfk通过关闭一种叫做PTEN的肿瘤抑制因子的抗肿瘤活性而导致癌症。我们通过发现SFKs如何关闭PTEN活性来补充他们的发现- SFKs通过一种称为磷酸化的化学修饰过程关闭PTEN活性。在这个应用中，我们建议研究SFKs如何修饰PTEN以及磷酸化如何关闭PTEN的肿瘤抑制活性。综上所述，我们的研究将有助于开发两种类型的抗癌疗法：(i)模拟CHK结合和抑制SFKs的疗法，以及（ii）干扰SFKs磷酸化PTEN的疗法。

Normal cell growth and division are governed by the balanced action of two groups of enzymes - the enzymes encoded by the proto-oncogenes (precursors of cancer-causing genes) and the tumour suppressor genes. Abnormalities in the regulation of these enzymes cause cancer. Indeed, over-stimulation of a group of proto-oncogenic enzymes called the Src-family kinases (SFKs) is the major contributing factor to most human cancers. In this application, we propose to study how inactivation of SFKs by their native inhibitor CHK suppresses cancer formation and how over-stimulation of SFKs causes cancer. Exactly how CHK inactivates SFKs remains unclear. Recently, we discovered a novel mechanism employed by CHK to inhibit SFKs. In this mechanism, CHK binds to SFKs tightly and the binding alone is sufficient to completely shut down SFK activity. As this novel inhibitory mechanism of CHK can be exploited for the development of synthetic SFK inhibitors for cancer treatment, we propose to unravel how CHK tightly binds to SFKs and how the binding inhibits the cancer-promoting activity of SFKs. How over-stimulation of SFKs induces the development of human cancer has been an important outstanding question in cancer research. Recently, we and two groups of researchers in Texas achieved breakthroughs in answering this question. The Texan groups discovered that the over-stimulated SFKs cause cancer by shutting down the anti-tumour activity of a tumour suppressor called PTEN. We complemented their findings by discovering how SFKs shut down PTEN activity - SFKs shut down PTEN activity by a chemical modification process called phosphorylation. In this application, we propose to study how SFKs modify PTEN and how phosphorylation shuts down the tumour suppressor activity of PTEN. In summary, our studies will benefit the development of two types of anti-cancer therapeutics: (i) those mimicking CHK binding and inhibition of SFKs, and (ii) those interfering with phosphorylation of PTEN by SFKs.