Journal Article

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

Darrin P. Smith, Sydonia I. Rayter, Christiane Niederlander, James Spicer, C. Mike Jones and Alan Ashworth

in Human Molecular Genetics

Volume 10, issue 25, pages 2869-2877
Published in print December 2001 | ISSN: 0964-6906
Published online December 2001 | e-ISSN: 1460-2083 | DOI:
LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1

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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 TGFβ superfamily members and their downstream effectors. A possible role for LIP1 and LKB1 in TGFβ signalling is supported by the observation that LIP1 interacts with the TGFβ-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.

Journal Article.  6026 words.  Illustrated.

Subjects: Genetics and Genomics

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