Downstream of human NDR kinases: Impacting on c-myc and p21 protein stability to control cell cycle progression

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2011-06, Vol.10 (12), p.1897-1904
• Main Authors: Cornils, Hauke, Kohler, Reto S., Hergovich, Alexander, Hemmings, Brian A.
• Format: Article
• Language: English
• Subjects: Animals; Binding; Biology; Bioscience; Calcium; Cancer; Cell; Cell Cycle; Cycle; Cyclin-Dependent Kinase Inhibitor p21 - physiology; Humans; Landes; Organogenesis; Protein Stability; Protein-Serine-Threonine Kinases - physiology; Proteins; Proto-Oncogene Proteins c-myc - physiology; Tumor Suppressor Proteins - physiology
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.10.12.15826

The mammalian genome encodes four members of the NDR/LATS kinase family: NDR1 (STK38), NDR2 (STK38L), LATS1 and LATS2, which are highly conserved from yeast to man. Members of the NDR/LATS kinase family have been implicated in a variety of biological processes ranging from cell division and morphology to apoptosis and tumor suppression. In mammals, LATS1/2 function as central parts of the HIPPO tumor suppressor pathway by restricting the activity of the YAP/TAZ proto-oncogenes. Recent evidence suggested that NDR1/2 are also part of an extended HIPPO tumor suppressor pathway. Apart from functions in apoptosis signaling and tumor suppression, NDR1/2 have been implicated in controlling centrosome duplication and mitotic chromosome alignment downstream of the HIPPO kinase homologs MST1 and MST2. Significantly, we also reported recently that NDR1/2 are controlling G 1 /S transition downstream of a third MST family member MST3. Intriguingly, this newly described MST3-NDR1/2 axis promotes G 1 progression by stabilizing c-myc and preventing p21 accumulation, indicating a potential pro-tumorigenic role for NDR kinases. Here, we discuss these novel cell cycle functions of NDR kinases in a broader context and elaborate on possible explanations for the opposing functions of NDR kinases in normal and tumor biology.