LKB1-dependent signaling pathways.
This review focuses on remarkable recent findings concerning the mechanism by which the LKB1 protein kinase that is mutated in Peutz-Jeghers cancer syndrome operates as a tumor suppressor. We discuss evidence that the cellular localization and activity of LKB1 is controlled through its interaction with a catalytically inactive protein resembling a protein kinase, termed STRAD, and an armadillo repeat-containing protein, named mouse protein 25 (MO25). The data suggest that LKB1 functions as a tumor suppressor by not only inhibiting proliferation, but also by exerting profound effects on cell polarity and, most unexpectedly, on the ability of a cell to detect and respond to low cellular energy levels. Genetic and biochemical findings indicate that LKB1 exerts its effects by phosphorylating and activating 14 protein kinases, all related to the AMP-activated protein kinase. The work described in this review shows how a study of an obscure cancer syndrome can uncover new and important regulatory pathways, relevant to the understanding of multiple human diseases.
Alessi
Dario R
DR
Medical Research Council, Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland. d.r.alessi@dundee.ac.uk
Sakamoto
Kei
K
Bayascas
Jose R
JR
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D016764:Cell Polarity; D004789:Enzyme Activation; D016147:Genes, Tumor Suppressor; D006801:Humans; D007527:Isoenzymes / Q000145:classification / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000145:classification / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010580:Peutz-Jeghers Syndrome / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D010802:Phylogeny; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D007527:Isoenzymes; D009097:Multienzyme Complexes; C476400:STRADA protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases