LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1

Hum Mol Genet. 2001 Dec 1;10(25):2869-77. doi: 10.1093/hmg/10.25.2869.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases
  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Carrier Proteins*
  • Cell Nucleus / enzymology
  • Chromosomes, Human, Pair 2 / genetics
  • Cytoplasm / enzymology
  • DNA-Binding Proteins / metabolism
  • Gene Expression
  • HeLa Cells / cytology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Peutz-Jeghers Syndrome / enzymology*
  • Peutz-Jeghers Syndrome / genetics
  • Precipitin Tests
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteins*
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Smad Proteins
  • Smad4 Protein
  • Trans-Activators / metabolism
  • Xenopus Proteins*
  • Xenopus laevis / embryology
  • Xenopus laevis / genetics
  • Xenopus laevis / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nerve Growth Factors
  • Peptide Fragments
  • Proteins
  • SMAD4 protein, human
  • STK11IP protein, human
  • Smad Proteins
  • Smad4 Protein
  • Smad4 protein, mouse
  • Stk11ip protein, mouse
  • Trans-Activators
  • Xenopus Proteins
  • smad4.1 protein, Xenopus
  • smad4.2 protein, Xenopus
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • Stk11 protein, mouse
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases

Associated data

  • GENBANK/AA134795