Cellular Redistribution of Protein Tyrosine Phosphatases LAR and PTPσ by Inducible Proteolytic Processing
Cellular Redistribution of Protein Tyrosine Phosphatases LAR and PTPσ by Inducible Proteolytic Processing
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通过诱导蛋白水解加工蛋白质酪氨酸磷酸酶 LAR 和 PTPσ 的细胞重新分布
作者：
B. Aicher;M. Lerch;T. Müller;J. Schilling;A. Ullrich
大多数受体样蛋白酪氨酸磷酸酶（PTPases）在其胞外区域与细胞粘附分子具有高度的同源性。我们研究了受体样PTPases LAR和PTPσ加工的功能意义。PTPσ的生物合成和细胞内加工与相关的PTPase LAR相似，并以双亚基复合物的形式在细胞表面表达。用钙离子载体A23187或磷酯TPA处理细胞后，LAR和PTPσ均发生进一步的蛋白水解。TPA在293细胞中诱导LAR加工确实需要过表达PKCα。诱导的蛋白水解导致两种PTPases的胞外结构域脱落。这与在氨基酸Pro821和Ile822之间鉴定出一个特定的PTPσ切割位点一致。共聚焦显微镜研究发现，粘附连接和桥粒是两种PTPases的首选亚细胞定位，与血小板红蛋白相匹配。与这一观察结果一致，我们发现血小板红蛋白和β-连环蛋白与体外LAR的细胞内结构域直接相关。综上所述，这些数据表明LAR和PTPσ与cadherin/catenin家族的细胞粘附分子一起参与细胞接触的调节。经过细胞外结构域的加工和脱落后，两种PTPases的催化活性细胞内部分被内化并重新分布到远离细胞-细胞接触部位的地方，这表明一种调节这些PTPases活性和靶特异性的机制。钙戒断导致细胞接触中断，也导致内化，但与先前的蛋白水解裂解和细胞外结构域的脱落无关。我们得出结论，LAR和PTPσ的亚细胞定位受到至少两种独立机制的调节，其中一种机制需要它们的细胞外结构域的存在，另一种机制涉及完整的细胞-细胞接触的存在。
Most receptor-like protein tyrosine phosphatases (PTPases) display a high degree of homology with cell adhesion molecules in their extracellular domains. We studied the functional significance of processing for the receptor-like PTPases LAR and PTPσ. PTPσ biosynthesis and intracellular processing resembled that of the related PTPase LAR and was expressed on the cell surface as a two-subunit complex. Both LAR and PTPσ underwent further proteolytical processing upon treatment of cells with either calcium ionophore A23187 or phorbol ester TPA. Induction of LAR processing by TPA in 293 cells did require overexpression of PKCα. Induced proteolysis resulted in shedding of the extracellular domains of both PTPases. This was in agreement with the identification of a specific PTPσ cleavage site between amino acids Pro821 and Ile822. Confocal microscopy studies identified adherens junctions and desmosomes as the preferential subcellular localization for both PTPases matching that of plakoglobin. Consistent with this observation, we found direct association of plakoglobin and β-catenin with the intracellular domain of LAR in vitro. Taken together, these data suggested an involvement of LAR and PTPσ in the regulation of cell contacts in concert with cell adhesion molecules of the cadherin/catenin family. After processing and shedding of the extracellular domain, the catalytically active intracellular portions of both PTPases were internalized and redistributed away from the sites of cell–cell contact, suggesting a mechanism that regulates the activity and target specificity of these PTPases. Calcium withdrawal, which led to cell contact disruption, also resulted in internalization but was not associated with prior proteolytic cleavage and shedding of the extracellular domain. We conclude that the subcellular localization of LAR and PTPσ is regulated by at least two independent mechanisms, one of which requires the presence of their extracellular domains and one of which involves the presence of intact cell–cell contacts.
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DOI：
10.1073/pnas.92.25.11686
发表时间：
1995-12-05
影响因子：
11.1
作者：
PULIDO, R;SERRAPAGES, C;STREULI, M
通讯作者：
STREULI, M
白细胞共同抗原相关受体连接酪氨酸磷酸酶。
DOI：
--
发表时间：
1993
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Longo,FM;Martignetti,JA;LeBeau,JM;Zhang,JS;Barnes,JP;Brosius,J
通讯作者：
Brosius,J
LAR 跨膜蛋白酪氨酸磷酸酶的前蛋白加工、亚基关联和脱落的突变分析。
DOI：
--
发表时间：
1994
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Serra-Pages,C;Saito,H;Streuli,M
通讯作者：
Streuli,M
影响因子：
7.5
作者：
BRADYKALNAY, SM;TONKS, NK
通讯作者：
TONKS, NK
人类 LAR 蛋白酪氨酸磷酸酶基因的基因组组织和细胞外纤连蛋白 III 型结构域中的选择性剪接。
DOI：
--
发表时间：
1994
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
O'Grady,P;Krueger,NX;Streuli,M;Saito,H
通讯作者：
Saito,H