Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD

A. F. Baas, J. Boudeau, G. P. Sapkota, L Smit, R. Medema, N. A. Morrice, D. R. Alessi, H. C. Clevers

    Research output: Contribution to journalArticle

    269 Citations (Scopus)

    Abstract

    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 G1 arrest. Our results imply that STRAD plays a key role in regulating the tumour suppressor activities of LKB1.

    Original languageEnglish
    Pages (from-to)3062-3072
    Number of pages11
    JournalEMBO Journal
    Volume22
    Issue number12
    DOIs
    Publication statusPublished - 2003

    Fingerprint Dive into the research topics of 'Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD'. Together they form a unique fingerprint.

  • Cite this

    Baas, A. F., Boudeau, J., Sapkota, G. P., Smit, L., Medema, R., Morrice, N. A., Alessi, D. R., & Clevers, H. C. (2003). Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO Journal, 22(12), 3062-3072. https://doi.org/10.1093/emboj/cdg292