公开(公告)号：US20130040894A1

公开(公告)日：2013-02-14

申请号：US13500902

申请日：2010-10-06

申请人： Priit Kogerman ,  Alla Maloverjan ,  Marko Piirsoo ,  Piret Michelson ,  Torben Osterlund

发明人： Priit Kogerman ,  Alla Maloverjan ,  Marko Piirsoo ,  Piret Michelson ,  Torben Osterlund

IPC分类号： C12N9/99 ,  C12N5/076 ,  C12N5/09 ,  C07K2/00 ,  A61P19/00 ,  A61K38/02 ,  A61P35/00 ,  A61K31/7088 ,  A61P15/08 ,  A61P17/14 ,  C12N5/071 ,  C07K7/08

CPC分类号： C12N9/1205 ,  A61K48/00

摘要： The present invention relates to human serine/threonine kinase ULK3 and its ability to regulate GLI transcription factors; mediators of SHH signaling. This disclosure demonstrates that ULK3 enhances endogenous and over-expressed GLI1 and GLI2 transcriptional activity in cultured cells, and ULK3 alters subcellular localization of GLI1. According to this disclosure ULK3 is an autophosphorylated kinase and phosphorylates GLI proteins in vitro. A peptide sequence in GLI1 C-terminus that is phosphorylated by ULK3 is provided in this disclosure. ULK3 catalytical activity is shown to be crucial for its function in SHH pathway. This disclosure shows that serine/threonine kinase ULK3 is involved in the SHH pathway as a positive regulator of GLI proteins. Furthermore, a therapeutic method in SHH dependent human disorders is disclosed by pharmacological inhibition of ULK3 kinase activity. Identification of ULK3 substrate sequence in GLI1 allows the design of peptide-based modulators of its kinase activity.

摘要翻译： 本发明涉及人丝氨酸/苏氨酸激酶ULK3及其调节GLI转录因子的能力; SHH信号传导介质。 本公开表明ULK3增强培养细胞中内源性和过度表达的GLI1和GLI2转录活性，并且ULK3改变GLI1的亚细胞定位。 根据该公开内容，ULK3是一种自磷酸化激酶，并在体外磷酸化GLI蛋白。 在本公开中提供了通过ULK3磷酸化的GLI1 C-末端中的肽序列。 显示ULK3催化活性对其在SHH途径中的功能至关重要。 本公开显示丝氨酸/苏氨酸激酶ULK3作为GLI蛋白的阳性调节因子参与SHH途径。 此外，通过对ULK3激酶活性的药理学抑制来揭示SHH依赖性人类疾病中的治疗方法。 鉴定GLI1中的ULK3底物序列允许基于肽的调节剂设计其激酶活性。