Modulation of Rho Guanine Exchange Factor Lfc Activity by Protein Kinase A-Mediated Phosphorylation
Modulation of Rho Guanine Exchange Factor Lfc Activity by Protein Kinase A-Mediated Phosphorylation
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DOI：
10.1128/mcb.01268-08
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发表时间：
2009-11-01
影响因子：
5.3
通讯作者：
Rottapel, Robert
中科院分区：
文献类型：
--
作者：
Meiri, David;Greeve, Melissa A.;Rottapel, Robert
Lfc是Rho的鸟嘌呤核苷酸交换因子（GEF），其表现出与微管缔合的不寻常的能力。虽然在Lfc多肽中检测到几个磷酸化残基，但磷酸化调节Lfc交换活性的机制仍不清楚。我们证实Lfc是一个磷酸化的蛋白质，并证明14-3-3直接相互作用，并在磷酸化依赖的方式与Lfc。我们确定AKAP 121作为Lfc结合蛋白，并表明Lfc是磷酸化的AKAP依赖的方式由蛋白激酶A（PKA）。毛喉素处理诱导14-3-3与Lfc结合，并抑制野生型Lfc对RhoA的交换活性。重要的是，Lfc的突变体不能与14-3-3蛋白结合，对毛喉素的抑制有抗性。Tctex-1是一种动力蛋白马达轻链，以与14-3-3竞争的方式与Lfc结合。
Lfc is a guanine nucleotide exchange factor (GEF) for Rho that demonstrates an unusual ability to associate with microtubules. While several phosphorylated residues have been detected in the Lfc polypeptide, the mechanism(s) by which phosphorylation regulates the exchange activity of Lfc remains unclear. We confirm that Lfc is a phosphorylated protein and demonstrate that 14-3-3 interacts directly and in a phosphorylation-dependent manner with Lfc. We identify AKAP121 as an Lfc-binding protein and show that Lfc is phosphorylated in an AKAP-dependent manner by protein kinase A (PKA). Forskolin treatment induced 14-3-3 binding to Lfc and suppressed the exchange activity of wild-type Lfc on RhoA. Importantly, a mutant of Lfc that is unable to associate with 14-3-3 proteins was resistant to inhibition by forskolin. Tctex-1, a dynein motor light chain, binds to Lfc in a competitive manner with 14-3-3.