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首页> 外文期刊>Molecular and Cellular Biology >Localization of Atypical Protein Kinase C Isoforms into Lysosome-Targeted Endosomes through Interaction with p62
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Localization of Atypical Protein Kinase C Isoforms into Lysosome-Targeted Endosomes through Interaction with p62

机译：通过与p62相互作用将非典型蛋白激酶C同工型定位为溶酶体靶向的内体。

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An increasing number of independent studies indicate that the atypical protein kinase C (PKC) isoforms (aPKCs) are critically involved in the control of cell proliferation and survival. The aPKCs are targets of important lipid mediators such as ceramide and the products of the PI 3-kinase. In addition, the aPKCs have been shown to interact with Ras and with two novel proteins, LIP (lambda-interacting protein; a selective activator of λ/ιPKC) and the product ofpar-4 (a gene induced during apoptosis), which is an inhibitor of both λ/ιPKC and ζPKC. LIP and Par-4 interact with the zinc finger domain of the aPKCs where the lipid mediators have been shown to bind. Here we report the identification of p62, a previously described phosphotyrosine-independent p56lckSH2-interacting protein, as a molecule that interacts potently with the V1 domain of λ/ιPKC and, albeit with lower affinity, with ζPKC. We also show in this study that ectopically expressed p62 colocalizes perfectly with both λ/ιPKC and ζPKC. Interestingly, the endogenous p62, like the ectopically expressed protein, displays a punctate vesicular pattern and clearly colocalizes with endogenous λ/ιPKC and endogenous ζPKC. P62 colocalizes with Rab7 and partially with lamp-1 and limp-II as well as with the epidermal growth factor (EGF) receptor in activated cells, but not with Rab5 or the transferrin receptor. Of functional relevance, expression of dominant negative λ/ιPKC, but not of the wild-type enzyme, severely impairs the endocytic membrane transport of the EGF receptor with no effect on the transferrin receptor. These findings strongly suggest that the aPKCs are anchored by p62 in the lysosome-targeted endosomal compartment, which seems critical for the control of the growth factor receptor trafficking. This is particularly relevant in light of the role played by the aPKCs in mitogenic cell signaling events.
机译：越来越多的独立研究表明，非典型蛋白激酶C（PKC）亚型（aPKCs）关键参与细胞增殖和存活的控制。 aPKC是重要脂质介体的靶标，例如神经酰胺和PI 3-激酶的产物。此外，已显示aPKC与Ras和两种新蛋白LIP（λ相互作用蛋白;λ/ιPKC的选择性激活剂）和 par-4 （一个基因）的产物相互作用。 （在凋亡期间被诱导），其是λ/λPKC和ζPKC的抑制剂。 LIP和Par-4与aPKC的锌指结构域相互作用，在该结构中脂质介体已结合。在这里，我们报告了p62的鉴定，p62是先前描述的不依赖磷酸酪氨酸的p56 lck SH2相互作用蛋白，是与λ/ιPKC的V1结构域有效相互作用的分子，并且，尽管与ζPKC的亲和力较低。我们还在这项研究中表明，异位表达的p62与λ/ιPKC和ζPKC完美共定位。有趣的是，内源性p62，如异位表达的蛋白质一样，显示出点状的囊泡模式，并且明显地与内源性λ/ IPKC和内源性ζPKC共定位。在活化细胞中，P62与Rab7共定位，并与lamp-1和limp-II以及表皮生长因子（EGF）受体共定位，但与Rab5或转铁蛋白受体共定位。具有功能相关性，显性负λ/ PKC而不是野生型酶的表达严重损害了EGF受体的内吞膜转运，而对运铁蛋白受体没有影响。这些发现强烈表明，aPKC被p62锚定在溶酶体靶向的内体区室中，这对于控制生长因子受体的运输似乎至关重要。鉴于aPKC在有丝分裂细胞信号转导事件中所起的作用，这尤其重要。

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