Loss of cytoplasmic retention ability of mutant LKB1 found in Peutz-Jeghers syndrome patients.
LKB1 Serine/Threonine (ST) kinase (also called STK11) originally identified in our novel protein kinase search project has recently been recognized as a susceptibility gene of Peutz-Jeghers Syndrome (PJS; MIM 175200). PJS is a dominantly inherited human disorder which is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin pigmentation. Since PJS patients also show a predisposition to a wide spectrum of cancers, it is speculated that LKB1 has a tumor suppressor function. In the present study we have characterized the basic biochemical property of LKB1. In the analysis of mutant LKB1 identified in PJS patients, it was found that one of the mutants, SL26, does not lose its kinase function, but alters its subcellular distribution to accumulate in the nucleus only, whereas wild type LKB1 shows both nuclear and cytoplasmic localization. Domain mapping of the nuclear targeting signal of LKB1 assigned it to its amino terminal side. Furthermore, it was shown that LKB1 also has a cytoplasmic retention ability which is considered defective and pathogenic in the SL26 mutant. It is speculated that subcellular distribution of LKB1 is regulated in the balance of these two forces, importation into the nucleus and retention within the cytoplasm; and the cytoplasmic retention ability is necessary for LKB1 to fulfil its normal function.
Nezu
J
J
Chugai Research Institute for Molecular Medicine Inc., 153-2 Nagai Niihari, Ibaraki, 300-4101, Japan. nezuj@cimmed.com
Oku
A
A
Shimane
M
M
D000091162:AMP-Activated Protein Kinase Kinases; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells / Q000378:metabolism; D002413:Cations, Divalent; D002467:Cell Nucleus / Q000201:enzymology; D016384:Consensus Sequence; D003593:Cytoplasm / Q000201:enzymology*; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry; D010580:Peutz-Jeghers Syndrome / Q000201:enzymology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D002413:Cations, Divalent; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases