Human Molecular Genetics, 2001, Vol. 10, No. 25 2869-2877
© 2001 Oxford University Press
LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1
1The Breakthrough Toby Robins Breast Cancer Research Centre and 2Section of Gene Function and Regulation, Chester Beatty Laboratories, Institute of Cancer Research, Fulham Road, London SW3 6JB, UK
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 TGFß superfamily members and their downstream effectors. A possible role for LIP1 and LKB1 in TGFß signalling is supported by the observation that LIP1 interacts with the TGFß-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.
+ To whom correspondence should be addressed. Tel: +44 20 7970 6058; Fax: +44 20 7878 3858; Email alana@icr.ac.uk
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