LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1.
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.
Smith
D P
DP
The Breakthrough Toby Robins Breast Cancer Research Centre, London, UK.
Rayter
S I
SI
Niederlander
C
C
Spicer
J
J
Jones
C M
CM
Ashworth
A
A
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins; D002467:Cell Nucleus / Q000201:enzymology; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D003593:Cytoplasm / Q000201:enzymology; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006367:HeLa Cells / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D010580:Peutz-Jeghers Syndrome / Q000201:enzymology* / Q000235:genetics; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051785:Smad Proteins; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D011506:Proteins; C497796:SMAD4 protein, human; C491653:STK11IP protein, human; D051785:Smad Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C491655:Stk11ip protein, mouse; D015534:Trans-Activators; D029867:Xenopus Proteins; C490808:smad4.1 protein, Xenopus; C117263:smad4.2 protein, Xenopus; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases