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首页> 外文期刊>Cellular Signalling >In addition to the SH3 binding region, multiple regions within the N-terminal noncatalytic portion of the cAMP-specific phosphodiesterase, PDE4A5, contribute to its intracellular targeting
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In addition to the SH3 binding region, multiple regions within the N-terminal noncatalytic portion of the cAMP-specific phosphodiesterase, PDE4A5, contribute to its intracellular targeting

机译：除了SH3结合区域外，cAMP特异性磷酸二酯酶PDE4A5 N末端非催化部分的多个区域也有助于其细胞内靶向

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The long cyclic AMP (cAMP)-specific phosphodiesterase isoform. PDE4A5 (PDE4A subfamily isoform variant 5), Mien transiently expressed in COS-7 cells. was shown in subcellular fractionation studies to be associated with both membrane and cytosol fractions, with immunofluorescence analyses identifying PDE4A5 as associated both with ruffles at the cell margin and also at a distinct perinuclear localisation. Deletion of the first nine amino acids of PDE4A5 (1) ablated its ability to interact with the SH3 domain of the tyrosyl kinase, LYN: (2) reduced, but did not ablate, membrane association: and (3) disrupted the focus of PDE4A5 localisation within ruffles at the cell margin. This deleted region contained a Class 1 SH3 binding motif of similar sequence to those identified by screening a phage display library with the LYN-SH3 domain. Truncation to remove the PDE4A5 isoform-specific N-terminal region caused a further reduction in membrane association and ablated localisation at the cell margin. Progressive truncation to delete the PDE4A long isoform common region and then the long isoform-specific UCR1 did not cause any further change in membrane association or intracellular distribution. However, deletion up to the super-short form splice junction generated an entirely soluble 'core' PDE4A species, We propose that multiple sites in the N-terminal noncatalytic portion of PDE4A5 have the potential to associate with intracellular structures and thus define its intracellular localisation. At least two such sites lie within the PDE4A5 isoform-specific N-terminal region and these appear to be primarily responsible for targeting PDE4A5 to, and organising it within. the cell margin: one is an SH3 binding motif able to interact with LYN kinase and the other lies within the C-terminal portion of the PDE4A5 unique region. A third membrane association region is located within the N-terminal portion of UCR2 and appears to be primarily responsible for targeting to the perinuclear region. Progressive N-terminal truncation. to delete defined regions of PDE4A5, identified activity changes occurring upon deletion of the SH3 binding site region and then upon deletion of the membrane association site region located within UCR2. This suggests that certain of these anchor sites may not only determine intracellular targeting but may also transduce regulatory effects on PDE4A5 activity. (C) 2002 Elsevier Science Inc. All rights reserved. [References: 67]
机译：长环AMP（cAMP）特异性磷酸二酯酶同工型。 Mien在COS-7细胞中瞬时表达的PDE4A5（PDE4A亚家族亚型变异体5）。在亚细胞分级研究中显示，PDE4A5与膜和胞质溶胶级分相关，免疫荧光分析确定PDE4A5与细胞边缘的褶皱以及在不同的核周位置均相关。 PDE4A5的前九个氨基酸的删除（1）消除了其与酪氨酰激酶SH3结构域相互作用的能力，LYN：（2）减少但未消除，膜缔合：和（3）破坏了PDE4A5的研究重点褶皱在细胞边缘的定位。该缺失的区域含有与通过筛选具有LYN-SH3结构域的噬菌体展示文库鉴定的序列相似的序列的1类SH3结合基序。截短以去除PDE4A5同工型特异的N-末端区域导致膜结合的进一步减少和细胞边缘的消融定位。逐步截短以删除PDE4A长同工型共同区域，然后长同工型特异的UCR1不会引起膜结合或细胞内分布的任何进一步变化。然而，直至超短形式剪接连接的缺失都产生了完全可溶的“核心” PDE4A物种。我们提出，PDE4A5的N末端非催化部分中的多个位点可能与细胞内结构缔合，从而定义了其细胞内定位。至少两个这样的位点位于PDE4A5同工型特异性N端区域内，这些位点似乎主要负责将PDE4A5靶向并在其中进行组织。细胞边缘：一个是能够与LYN激酶相互作用的SH3结合基序，另一个位于PDE4A5独特区域的C端部分。第三膜缔合区位于UCR2的N末端部分内，并且似乎主要负责靶向核周区。进行性N末端截短。为了删除PDE4A5的定义区域，在删除SH3结合位点区域后，然后在删除位于UCR2内的膜结合位点区域时，发生了确定的活性变化。这表明这些锚定位点中的某些不仅可以确定细胞内靶向，而且还可以转导对PDE4A5活性的调节作用。 （C）2002 Elsevier Science Inc.保留所有权利。 [参考：67]

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