CDK5RAP3结合PHLPP调控AKT去磷酸化抑制胃癌发展的机制研究

Our previous studies have confirmed CDK5RAP3 was down-regμlated in gastric cancer. Low expression of CDK5RAP3 was correlated with poorer prognosis. CDK5RAP3 expression level was an independent prognostic factor of gastric cancer patients. CDK5RAP3 inhibited gastric cancer cell proliferation, invasion and metastasis by promoting the degradation of β-catenin. Furthermore, we found that CDK5RAP3 could interact with AKT in the co-immunoprecipitation assay. Also, CDK5RAP3 led to AKT dephosphorylation at the point of Ser473. Therefore, we hypothesize that the CDK5RAP3-AKT protein complex is critical for the ability of recruiting protein phosphatase PHLPP and promoting AKT dephosphorylation at Ser473. This study may provide new candidate targets and interventions for the treatment of gastric cancer.

本课题组前期研究发现CDK5RAP3在胃癌中呈低表达，预后差，CDK5RAP3的表达水平是胃癌患者独立的预后影响因素。CDK5RAP3通过促进β-catenin的降解，达到抑制胃癌细胞增殖、侵袭与转移的作用。进一步我们发现，CDK5RAP3可与AKT免疫共沉淀，导致AKT的Ser473位点去磷酸化。因此本项目拟在前期研究的基础上提出以下科学假说：CDK5RAP3与AKT形成蛋白复合体，并招募蛋白磷酸酶PHLPP，促进AKT的Ser473位点去磷酸化，发挥其抑癌基因功能。本研究将进一步揭示CDK5RAP3抑制胃癌的机制理论，为抗胃癌靶向药物设计提供新思路。

本课题组前期研究发现CDK5RAP3通过GSK-3β的Ser9位点去磷酸化，促进β-catenin的Ser37/Thr41位点磷酸化，加快β-catenin的降解，达到抑制胃癌细胞增殖、侵袭与转移的作用。但目前仍不清楚CDK5RAP3对GSK-3β的Ser9位点去磷酸化的具体机制。据此，本课题组就CDK5RAP3调控AKT磷酸化的具体机制进行了深入探讨，我们研究发现，CDK5RAP3抑制AKT磷酸化，从而促进GSK-3β磷酸化以及抑制β-catenin蛋白的表达，进而在胃癌中扮演着抑癌作用。此外，我们还就CDK5RAP3在胃癌中发挥抑癌作用的具体机制进行了多项研究。然而，CDK5RAP3在胃癌肿瘤微环境中发挥的免疫调节作用尚未见报道。据此，本课题组针对胃癌中多个免疫抑制蛋白以及CDK5RAP3在肿瘤微环境中的免疫调节作用开展了一系列研究。