NDR kinase is activated by RASSF1A/MST1 in response to Fas receptor stimulation and promotes apoptosis.
Human NDR1 and 2 (NDR1/2) are serine-threonine protein kinases in a subgroup of the AGC kinase family. The mechanisms of physiological NDR1/2 activation and their function remain largely unknown. Here we report that Fas and TNF-alpha receptor stimulation activates human NDR1/2 by promoting phosphorylation at the hydrophobic motif (Thr444/442). Moreover, NDR1/2 are essential for Fas receptor-induced apoptosis as shown by the fact that NDR knockdown significantly reduced cell death whereas overexpression of the NDR1 kinase further potentiated apoptosis. Activation of NDR1/2 by death receptor stimulation is mediated by the tumor suppressor RASSF1A. Furthermore, RASSF1A-induced apoptosis largely depends on the presence of NDR1/2. Fas receptor stimulation promoted direct phosphorylation and activation of NDR1/2 by the mammalian STE20-like kinase 1 (MST1), a downstream effector of RASSF1A. Concurrently, the NDR1/2 coactivator MOB1 induced MST1-NDR-MOB1 complex formation, which is crucial for MST1-induced NDR1/2 phosphorylation upon induction of apoptosis. Our findings identify NDR1/2 as novel proapoptotic kinases and key members of the RASSF1A/MST1 signaling cascade.
Vichalkovski
Anton
A
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Gresko
Ekaterina
E
Cornils
Hauke
H
Hergovich
Alexander
A
Schmitz
Debora
D
Hemmings
Brian A
BA
D017209:Apoptosis; D002460:Cell Line; D004789:Enzyme Activation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; C411762:RASSF1 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases; C491614:STK38 protein, human; C496014:STK38L protein, human