蛋白质磷酸酶1（PP-1）对转录因子Pax-6的功能修饰
摘要
Pax-6是进化上一个保守而重要的转录因子，它在眼睛与大脑发育中起着主导基因的作用，决定着人类，小鼠，斑马鱼和果蝇的晶体细胞分化。
到目前为止，不同形式的Pax-6已被发现，它们有着不同的分子量。但这并不意味着它们中的全部都已经被仔细的研究过，也并不意味着它们的蛋白质翻译后修饰作用被完整的诠释。前人的研究已经表明Pax-6是一个磷酸化蛋白，它受ERK，p38和HIPK2这三种激酶作用而发生磷酸化，并且它在磷酸化以后能大大的激活其转录的活性。然而，其去磷酸化修饰作用却不为人所知。
为了了解Pax-6的脱磷酸化修饰作用，作者首先研究了蛋白质丝氨酸／苏氨酸磷酸酶使Pax-6脱磷酸化的可能性。研究结果表明，PP-1和PP-2A这两种蛋白质磷酸酶均能在体外使Pax-6脱磷酸化。第二，作者检测了是否PP-1与PP-2A这两种蛋白质磷酸酶能特异地在体内使Pax-6脱去磷酸基团。结果表明，只有PP-1能与Pax-6在体内发生反应，使其脱磷酸化。第三，通过免疫共沉降的办法，作者发现细胞内的大部分Pax-6与PP-1的α催化亚基，或者β催化亚基结合在一块；然而只有少量的α催化亚基或者β催化亚基与Pax-6结合；PP-2A的A，B，C三种亚基与Pax-6没有相互作用。第四，随着Calyculin A这种PP-1抑制剂处理浓度的提高，与Pax-6结合的PP-1α催化亚基或者β催化亚基依次减少。当在人类晶体上皮细胞(HLE)中高表达PP-1α时，Pax-6的脱磷酸化增强；而此时用Calyculin A处理则能在一定程度上缓解这种脱磷酸化的作用。最后，通过特异性RNAi干扰实验对内源性PP-1α催化亚基或者β催化亚基进行knock-down，作者发现Pax-6的磷酸化增强。
因此，作者得出以下结论：PP-1α催化亚基和β催化亚基均参与Pax-6的脱磷酸化作用来调节其功能，而细胞内多数Pax-6蛋白由于PP-1的脱磷酸化作用而处于一种失活的状态，这导致一种静态的平衡。
Pax-6 is an evolutionarily conserved transcription factorand acts high up in the regulatory hierarchy controlling eyeand brain development in human, mouse, zebrafish, andDrosophila.
Previous studies have shown that Pax-6 is aphosphoprotein and its phosphorylation by ERK, p38 andhomeodomain-interacting protein kinase 2 greatly enhances itstransactivation activity. However, the protein phosphatasesresponsible for the dephosphorylation of Pax-6 remain unknown.
Here, we present both in vitro and in vivo evidence toshow that protein serine/threonine phosphatase-1 is a majorphosphatase, which directly dephosphorylates Pax-6. First,purified protein phosphatase-1 directly dephosphorylates Pax-6 in vitro. Second, immunoprecipitation-linked Western blotrevealed that both protein phosphatase-1αand proteinphosphatase-1βinteract with Pax-6. Thirdly, overexpressionof protein phosphatase-1αin human lens epithelial cellsleads to dephosphorylation of Pax-6. Finally, inhibition ofprotein phosphatase-1 activity by calyculin A or knockdown ofprotein phosphatase-1αand protein phosphatase-1βby RNAileads to enhanced phosphorylation of Pax-6. Moreover, ourresults also demonstrate that dephosphorylation of Pax-6 byprotein phosphatase-1 significantly modulates its function inregulating expression of both exogenous and endogenous genes.These results demonstrate that PP-1 acts as a major phosphatase to dephosphorylate Pax-6 and modulate itsfunction.
到目前为止，不同形式的Pax-6已被发现，它们有着不同的分子量。但这并不意味着它们中的全部都已经被仔细的研究过，也并不意味着它们的蛋白质翻译后修饰作用被完整的诠释。前人的研究已经表明Pax-6是一个磷酸化蛋白，它受ERK，p38和HIPK2这三种激酶作用而发生磷酸化，并且它在磷酸化以后能大大的激活其转录的活性。然而，其去磷酸化修饰作用却不为人所知。
为了了解Pax-6的脱磷酸化修饰作用，作者首先研究了蛋白质丝氨酸／苏氨酸磷酸酶使Pax-6脱磷酸化的可能性。研究结果表明，PP-1和PP-2A这两种蛋白质磷酸酶均能在体外使Pax-6脱磷酸化。第二，作者检测了是否PP-1与PP-2A这两种蛋白质磷酸酶能特异地在体内使Pax-6脱去磷酸基团。结果表明，只有PP-1能与Pax-6在体内发生反应，使其脱磷酸化。第三，通过免疫共沉降的办法，作者发现细胞内的大部分Pax-6与PP-1的α催化亚基，或者β催化亚基结合在一块；然而只有少量的α催化亚基或者β催化亚基与Pax-6结合；PP-2A的A，B，C三种亚基与Pax-6没有相互作用。第四，随着Calyculin A这种PP-1抑制剂处理浓度的提高，与Pax-6结合的PP-1α催化亚基或者β催化亚基依次减少。当在人类晶体上皮细胞(HLE)中高表达PP-1α时，Pax-6的脱磷酸化增强；而此时用Calyculin A处理则能在一定程度上缓解这种脱磷酸化的作用。最后，通过特异性RNAi干扰实验对内源性PP-1α催化亚基或者β催化亚基进行knock-down，作者发现Pax-6的磷酸化增强。
因此，作者得出以下结论：PP-1α催化亚基和β催化亚基均参与Pax-6的脱磷酸化作用来调节其功能，而细胞内多数Pax-6蛋白由于PP-1的脱磷酸化作用而处于一种失活的状态，这导致一种静态的平衡。
Pax-6 is an evolutionarily conserved transcription factorand acts high up in the regulatory hierarchy controlling eyeand brain development in human, mouse, zebrafish, andDrosophila.
Previous studies have shown that Pax-6 is aphosphoprotein and its phosphorylation by ERK, p38 andhomeodomain-interacting protein kinase 2 greatly enhances itstransactivation activity. However, the protein phosphatasesresponsible for the dephosphorylation of Pax-6 remain unknown.
Here, we present both in vitro and in vivo evidence toshow that protein serine/threonine phosphatase-1 is a majorphosphatase, which directly dephosphorylates Pax-6. First,purified protein phosphatase-1 directly dephosphorylates Pax-6 in vitro. Second, immunoprecipitation-linked Western blotrevealed that both protein phosphatase-1αand proteinphosphatase-1βinteract with Pax-6. Thirdly, overexpressionof protein phosphatase-1αin human lens epithelial cellsleads to dephosphorylation of Pax-6. Finally, inhibition ofprotein phosphatase-1 activity by calyculin A or knockdown ofprotein phosphatase-1αand protein phosphatase-1βby RNAileads to enhanced phosphorylation of Pax-6. Moreover, ourresults also demonstrate that dephosphorylation of Pax-6 byprotein phosphatase-1 significantly modulates its function inregulating expression of both exogenous and endogenous genes.These results demonstrate that PP-1 acts as a major phosphatase to dephosphorylate Pax-6 and modulate itsfunction.
引文
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