Protein phosphatase 2A cooperates with the autophagy-related kinase UNC-51 to regulate axon guidance in Caenorhabditis elegans
Protein phosphatase 2A cooperates with the autophagy-related kinase UNC-51 to regulate axon guidance in Caenorhabditis elegans
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DOI：
10.1242/dev.050708
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发表时间：
2010-05-15
期刊：
影响因子：
4.6
通讯作者：
Goshima, Yoshio
中科院分区：
文献类型：
--
作者：
Ogura, Ken-ichi;Okada, Takako;Goshima, Yoshio
UNC-51是一种丝氨酸/苏氨酸蛋白激酶，从酵母到人类都是保守的。酵母同系物Atg1调节饥饿生存所需的自噬(分解代谢膜运输)。在线虫中，UNC-51通过与其及其同系物用于自噬不同的机制来调节许多神经元的轴突引导。UNC-51调节UNC-5的亚细胞定位(运输)，UNC-5是轴突引导分子UNC-6/Netrin的受体；然而，UNC-51作用的分子细节在很大程度上尚不清楚。在这里，我们报告了UNC-51与LET-92的物理相互作用，LET-92是丝氨酸/苏氨酸蛋白磷酸酶2A(PP2A-C)的催化亚单位，在许多细胞功能中发挥重要作用。低等位基因剂量的let-92部分抑制弱但不严重的UNC-51突变体的轴突引导缺陷，低等位基因剂量的PP2A调节亚基A(PAA-1/PP2A-A)和B(SuR-6/PP2A-B)部分增强弱的UNC-51突变体。我们还发现，let-92可以非自主地作用于神经元的轴突引导，并且let-92与UNC-51在神经元中共定位。此外，PP2A还使被UNC-51磷酸化的磷酸蛋白去磷酸化。这些结果表明，通过形成复合体，PP2A与UNC-51合作，通过调节磷酸化来调节轴突引导。这是首次报道丝氨酸/苏氨酸蛋白磷酸酶在体内轴突引导中的作用。
UNC-51 is a serine/threonine protein kinase conserved from yeast to humans. The yeast homolog Atg1 regulates autophagy (catabolic membrane trafficking) required for surviving starvation. In C. elegans, UNC-51 regulates the axon guidance of many neurons by a different mechanism than it and its homologs use for autophagy. UNC-51 regulates the subcellular localization (trafficking) of UNC-5, a receptor for the axon guidance molecule UNC-6/Netrin; however, the molecular details of the role for UNC-51 are largely unknown. Here, we report that UNC-51 physically interacts with LET-92, the catalytic subunit of serine/threonine protein phosphatase 2A (PP2A-C), which plays important roles in many cellular functions. A low allelic dose of LET-92 partially suppressed axon guidance defects of weak, but not severe, unc-51 mutants, and a low allelic dose of PP2A regulatory subunits A (PAA-1/PP2A-A) and B (SUR-6/PP2A-B) partially enhanced the weak unc-51 mutants. We also found that LET-92 can work cell-non-autonomously on axon guidance in neurons, and that LET-92 colocalized with UNC-51 in neurons. In addition, PP2A dephosphorylated phosphoproteins that had been phosphorylated by UNC-51. These results suggest that, by forming a complex, PP2A cooperates with UNC-51 to regulate axon guidance by regulating phosphorylation. This is the first report of a serine/threonine protein phosphatase functioning in axon guidance in vivo.