Abstract
LKB1 is a serine/threonine kinase which is inactivated by mutation in the Peutz-Jeghers polyposis and cancer predisposition syndrome (PJS). We have identified a novel leucine-rich repeat containing protein, LIP1, that interacts with LKB1. The LIP1 gene consists of 25 exons, maps to human chromosome 2q36 and encodes a protein of 121 kDa. LIP1 appears to be a cytoplasmically located protein whereas we and others have shown previously that LKB1 is predominantly nuclear, with only a small proportion of cells showing strong cytoplasmic expression. However, when LKB1 and LIP1 are co-expressed, the proportion of cytoplasmic LKB1 dramatically increases, suggesting that LIP1 may regulate LKB1 function by controlling its subcellular localization. Ectopic expression of both LKB1 and LIP1 in Xenopus embryos induces a secondary body axis, providing further evidence for a functional link between the two proteins. This phenotype resembles the effects of ectopic expression of TGFbeta superfamily members and their downstream effectors. A possible role for LIP1 and LKB1 in TGFbeta signalling is supported by the observation that LIP1 interacts with the TGFbeta-regulated transcription factor SMAD4, forming a LKB1-LIP1-SMAD4 ternary complex. SMAD4 mutations give rise to juvenile polyposis syndrome, which is clinically similar to PJS. Our data suggest an unsuspected mechanistic link between these two syndromes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases
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Adaptor Proteins, Signal Transducing
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Amino Acid Sequence
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Animals
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Carrier Proteins*
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Cell Nucleus / enzymology
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Chromosomes, Human, Pair 2 / genetics
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Cytoplasm / enzymology
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DNA-Binding Proteins / metabolism
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Gene Expression
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HeLa Cells / cytology
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Humans
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Intracellular Signaling Peptides and Proteins
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Mice
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Molecular Sequence Data
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Mutation
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism*
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Peptide Fragments / genetics
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Peptide Fragments / metabolism*
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Peutz-Jeghers Syndrome / enzymology*
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Peutz-Jeghers Syndrome / genetics
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Precipitin Tests
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Protein Serine-Threonine Kinases / metabolism*
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Proteins*
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Sequence Homology, Amino Acid
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Signal Transduction
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Smad Proteins
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Smad4 Protein
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Trans-Activators / metabolism
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Xenopus Proteins*
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Xenopus laevis / embryology
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Xenopus laevis / genetics
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Xenopus laevis / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Nerve Growth Factors
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Peptide Fragments
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Proteins
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SMAD4 protein, human
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STK11IP protein, human
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Smad Proteins
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Smad4 Protein
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Smad4 protein, mouse
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Stk11ip protein, mouse
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Trans-Activators
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Xenopus Proteins
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smad4.1 protein, Xenopus
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smad4.2 protein, Xenopus
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Protein Serine-Threonine Kinases
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STK11 protein, human
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Stk11 protein, mouse
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases