Polarity-regulating Kinase Partitioning-defective 1b (PAR1b) Phosphorylates Guanine Nucleotide Exchange Factor H1 (GEF-H1) to Regulate RhoA-dependent Actin Cytoskeletal Reorganization*
Polarity-regulating Kinase Partitioning-defective 1b (PAR1b) Phosphorylates Guanine Nucleotide Exchange Factor H1 (GEF-H1) to Regulate RhoA-dependent Actin Cytoskeletal Reorganization*
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DOI：
10.1074/jbc.m111.267021
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发表时间：
2011-11
期刊：
影响因子：
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通讯作者：
Y. Yamahashi;Yasuhiro Saito;N. Murata‐Kamiya;M. Hatakeyama
中科院分区：
文献类型：
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作者：
Y. Yamahashi;Yasuhiro Saito;N. Murata‐Kamiya;M. Hatakeyama
背景：极性调节激酶PAR 1b也参与肌动蛋白细胞骨架的调节。结果：PAR 1b通过诱导S885和S959的磷酸化来抑制RhoA激活剂GEF-H1。结论：PAR 1b通过磷酸化依赖性调节GEF-H1来调控RhoA活性。意义：PAR 1b在细胞调节中协调微管和肌动蛋白细胞骨架系统。PAR 1b（Partitioning-deficient 1b），又称微管亲和调节激酶2（MARK 2），是进化上保守的PAR 1/MARK丝氨酸/苏氨酸激酶家族的成员，至少部分通过磷酸化微管相关蛋白（MAPs）来调节微管的稳定性，在细胞极性的建立和维持中发挥关键作用。PAR 1b也被报道影响肌动蛋白细胞骨架组织，提高了PAR 1b与Rho家族小GTP酶（肌动蛋白细胞骨架系统的中央调节因子）功能性相互作用的可能性。与这一概念相一致，最近发现PAR 1与RhoA特异性鸟嘌呤核苷酸交换因子H1（GEF-H1）物理相关。这一观察结果表明PAR 1b和GEF-H1之间存在功能联系。在这里，我们发现PAR 1b诱导GEF-H1在丝氨酸885和丝氨酸959上的磷酸化。我们还表明，PAR 1b诱导的丝氨酸885/丝氨酸959磷酸化抑制了GEF-H1的RhoA特异性GEF活性。因此，在两个丝氨酸残基上磷酸化的GEF-H1失去刺激RhoA的能力，从而不能诱导RhoA依赖性应力纤维形成。这些发现表明PAR 1b不仅通过MAP磷酸化调节微管稳定性，而且还通过诱导GEF-H1磷酸化影响肌动蛋白应激纤维的形成。PAR 1b在基于微管的细胞骨架系统和基于肌动蛋白的细胞骨架系统中协调调节细胞极性、细胞形态和细胞运动的双重功能。
Background: Polarity-regulating kinase PAR1b is also involved in regulation of the actin cytoskeleton. Results: PAR1b inhibits RhoA activator GEF-H1 by inducing phosphorylation on S885 and S959. Conclusion: PAR1b controls RhoA activity through phosphorylation-dependent regulation of GEF-H1. Significance: PAR1b coordinates the microtubule- and actin-cytoskeletal systems in cell regulation. Partitioning-defective 1b (PAR1b), also known as microtubule affinity-regulating kinase 2 (MARK2), is a member of evolutionally conserved PAR1/MARK serine/threonine kinase family, which plays a key role in the establishment and maintenance of cell polarity at least partly by phosphorylating microtubule-associated proteins (MAPs) that regulate microtubule stability. PAR1b has also been reported to influence actin cytoskeletal organization, raising the possibility that PAR1b functionally interacts with the Rho family of small GTPases, central regulators of the actin cytoskeletal system. Consistent with this notion, PAR1 was recently found to be physically associated with a RhoA-specific guanine nucleotide exchange factor H1 (GEF-H1). This observation suggests a functional link between PAR1b and GEF-H1. Here we show that PAR1b induces phosphorylation of GEF-H1 on serine 885 and serine 959. We also show that PAR1b-induced serine 885/serine 959 phosphorylation inhibits RhoA-specific GEF activity of GEF-H1. As a consequence, GEF-H1 phosphorylated on both of the serine residues loses the ability to stimulate RhoA and thereby fails to induce RhoA-dependent stress fiber formation. These findings indicate that PAR1b not only regulates microtubule stability through phosphorylation of MAPs but also influences actin stress fiber formation by inducing GEF-H1 phosphorylation. The dual function of PAR1b in the microtubule-based cytoskeletal system and the actin-based cytoskeletal system in the coordinated regulation of cell polarity, cell morphology, and cell movement.