LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1
LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1
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DOI：
10.1093/hmg/10.25.2869
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发表时间：
2001-12-01
影响因子：
3.5
通讯作者：
Ashworth, A
中科院分区：
文献类型：
--
作者：
Smith, DP;Rayter, SI;Ashworth, A
LKB1是一种丝氨酸/苏氨酸激酶，在Peutz-Jeghers息肉病和癌症易感综合征(PJS)中被突变失活。我们已经鉴定出一种新的富含亮氨酸重复序列的蛋白LIP1，它与LKB1相互作用。LIP1基因由25个外显子组成，定位于人类染色体2q36，编码121 kDa的蛋白质。LIP1似乎是一种位于细胞质的蛋白质，而我们和其他人之前已经证明LKB1主要是核的，只有一小部分细胞显示出强烈的细胞质表达。然而，当LKB1和LIP1共表达时，胞质LKB1的比例显著增加，提示LIP1可能通过控制LKB1的亚细胞定位来调节LKB1的功能。LKB1和LIP1在非洲爪哇胚胎中的异位表达诱导了第二体轴的形成，为这两种蛋白之间的功能联系提供了进一步的证据。这种表型类似于转化生长因子β超家族成员及其下游效应分子的异位表达所产生的影响。LIP1和LKB1可能在转化生长因子β信号转导中的作用被观察到LIP1与转化生长因子β调节的转录因子Smad4相互作用，形成LKB1-LIP1-Smad4三元复合体。Smad4基因突变导致幼年型息肉综合征，临床上类似于PJS。我们的数据表明，这两种综合征之间存在一种意想不到的机械性联系。
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 TGF beta superfamily members and their downstream effectors. A possible role for LIP1 and LKB1 in TGF beta signalling is supported by the observation that LIP1 interacts with the TGF beta -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.