Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD.
The LKB1 gene encodes a serine/threonine kinase mutated in Peutz-Jeghers cancer syndrome. Despite several proposed models for LKB1 function in development and in tumour suppression, the detailed molecular action of LKB1 remains undefined. Here, we report the identification and characterization of an LKB1-specific adaptor protein and substrate, STRAD (STe20 Related ADaptor). STRAD consists of a STE20- like kinase domain, but lacks several residues that are indispensable for intrinsic catalytic activity. Endogenous LKB1 and STRAD form a complex in which STRAD activates LKB1, resulting in phosphorylation of both partners. STRAD determines the subcellular localization of wild-type, but not mutant LKB1, translocating it from nucleus to cytoplasm. One LKB1 mutation previously identified in a Peutz-Jeghers family that does not compromise its kinase activity is shown here to interfere with LKB1 binding to STRAD, and hence with STRAD-dependent regulation. Removal of endogenous STRAD by siRNA abrogates the LKB1-induced G(1) arrest. Our results imply that STRAD plays a key role in regulating the tumour suppressor activities of LKB1.
Baas
A F
AF
Hubrecht Laboratory, Centre for Biomedical Genetics, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Boudeau
J
J
Sapkota
G P
GP
Smit
L
L
Medema
R
R
Morrice
N A
NA
Alessi
D R
DR
Clevers
H C
HC
D000091162:AMP-Activated Protein Kinase Kinases; D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D010580:Peutz-Jeghers Syndrome / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment; D013379:Substrate Specificity
D033942:Adaptor Proteins, Vesicular Transport; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D011993:Recombinant Fusion Proteins; C476400:STRADA protein, human; D029701:Saccharomyces cerevisiae Proteins; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D020930:MAP Kinase Kinase Kinases; C078754:STE20 protein, S cerevisiae; D000091162:AMP-Activated Protein Kinase Kinases