title: MICAL-1 is a negative regulator of MST-NDR kinase signaling and apoptosis.
abstract: MICALs (molecules interacting with CasL) are atypical multidomain flavoenzymes with diverse cellular functions. The molecular pathways employed by MICAL proteins to exert their cellular effects remain largely uncharacterized. Via an unbiased proteomics approach, we identify MICAL-1 as a binding partner of NDR (nuclear Dbf2-related) kinases. NDR1/2 kinases are known to mediate apoptosis downstream of the mammalian Ste-20-like kinase MST1, and ablation of NDR1 in mice predisposes the mice to cancer as a result of compromised apoptosis. MST1 phosphorylates NDR1/2 kinases at their hydrophobic motif, thereby facilitating full NDR kinase activity and function. However, if and how this key phosphorylation event is regulated are unknown. Here we show that MICAL-1 interacts with the hydrophobic motif of NDR1/2 and that overexpression or knockdown of MICAL-1 reduces or augments NDR kinase activation or activity, respectively. Surprisingly, MICAL-1 is a phosphoprotein but not an NDR or MST1 substrate. Rather, MICAL-1 competes with MST1 for NDR binding and thereby antagonizes MST1-induced NDR activation. In line with this inhibitory effect, overexpression or knockdown of MICAL-1 inhibits or enhances, respectively, NDR-dependent proapoptotic signaling induced by extrinsic stimuli. Our findings unveil a previously unknown biological role for MICAL-1 in apoptosis and define a novel negative regulatory mechanism of MST-NDR signaling.
authors: Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors: Yeping
authors: Y
authors: Zhou
authors: Youri
authors: Y
authors: Adolfs
authors: W W M Pim
authors: WW
authors: Pijnappel
authors: Stephen J
authors: SJ
authors: Fuller
authors: Roel C
authors: RC
authors: Van der Schors
authors: Ka Wan
authors: KW
authors: Li
authors: Peter H
authors: PH
authors: Sugden
authors: August B
authors: AB
authors: Smit
authors: Alexander
authors: A
authors: Hergovich
authors: R Jeroen
authors: RJ
authors: Pasterkamp
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007739:L Cells; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D000096985:Calponins; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D006899:Mixed Function Oxygenases; D017346:Protein Serine-Threonine Kinases; C455272:MICAL1 protein, human; D000096985:Calponins; C507541:Mical1 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C095566:STK4 protein, human; C552947:NDR1 protein kinase, mouse; C491614:STK38 protein, human