Regulation of the Wnt signalling component PAR1A by the Peutz-Jeghers syndrome kinase LKB1.
Loss-of-function mutations in the LKB1 (STK11) serine-threonine kinase gene cause Peutz-Jeghers syndrome, which is associated with inherited susceptibility to colorectal and other cancers. No downstream targets of LKB1 kinase activity have been identified. Here we show that LKB1 can direct the phosphorylation of the serine-threonine kinase PAR1A. The amino-acid residues phosphorylated as a result of LKB1 activity have been identified and phosphorylation at these residues is required for PAR1A kinase activity. PAR1A has previously been implicated as a positive regulator of the Wnt-betacatenin signalling pathway. We show here that LKB1 can modify transcription driven by the Wnt-regulated TCF response element, implicating LKB1 in a pathway known to play a key role in human colorectal tumorigenesis.
Spicer
James
J
Cancer Research UK Gene Function and Regulation Group, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK.
Rayter
Sydonia
S
Young
Neville
N
Elliott
Richard
R
Ashworth
Alan
A
Smith
Darrin
D
D000091162:AMP-Activated Protein Kinase Kinases; D000595:Amino Acid Sequence; D015179:Colorectal Neoplasms / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D010580:Peutz-Jeghers Syndrome / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C111833:MARK3 protein, human; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases