Tyrosyl phosphorylated serine-threonine kinase PAK1 is a novel regulator of prolactin-dependent breast cancer cell motility and invasion.
Tyrosyl phosphorylated serine-threonine kinase PAK1 is a novel regulator of prolactin-dependent breast cancer cell motility and invasion.
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DOI：
10.1007/978-3-319-12114-7_5
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发表时间：
2015
影响因子：
--
通讯作者：
Diakonova M
中科院分区：
文献类型：
--
作者：
Hammer A;Diakonova M
尽管努力发现调节乳腺癌转移的细胞途径，很少有人知道催乳素（PRL）如何与细胞外环境和细胞骨架蛋白调节乳腺癌细胞的运动和侵袭。我们暗示丝氨酸-苏氨酸激酶p21激活的激酶1（PAK 1）作为PRL激活的Janus激酶2（JAK 2）的新靶点。JAK 2依赖性PAK 1酪氨酰磷酸化在调节PAK 1激酶活性和PAK 1支架特性中起关键作用。酪氨酰磷酸化PAK 1通过至少两种机制促进PRL依赖性运动：桩蛋白/GIT 1/βPIX/pTyr-PAK 1复合物的形成，导致粘附转换增加和肌动蛋白结合蛋白细丝蛋白A的磷酸化。增加的粘附周转是细胞迁移的基础，磷酸化细丝蛋白A刺激PAK 1的激酶活性并增加肌动蛋白调节活性以促进细胞运动。酪氨酰磷酸化的PAK 1还通过以MAPK依赖性方式转录和分泌MMP-1和MMP-3，刺激乳腺癌细胞对PRL和三维（3D）胶原IV的侵袭。这些数据说明了乳腺癌细胞中PRL和细胞微环境之间的复杂相互作用，并表明PRL/PAK 1信号传导在乳腺癌转移中的关键作用。
Despite efforts to discover the cellular pathways regulating breast cancer metastasis, little is known as to how prolactin (PRL) cooperates with extracellular environment and cytoskeletal proteins to regulate breast cancer cell motility and invasion. We implicated serine-threonine kinase p21-activated kinase 1 (PAK1) as a novel target for PRL-activated Janus-kinase 2 (JAK2). JAK2-dependent PAK1 tyrosyl phosphorylation plays a critical role in regulation of both PAK1 kinase activity and scaffolding properties of PAK1. Tyrosyl phosphorylated PAK1 facilitates PRL-dependent motility via at least two mechanisms: formation of paxillin/GIT1/βPIX/pTyr-PAK1 complexes resulting in increased adhesion turnover and phosphorylation of actin-binding protein filamin A. Increased adhesion turnover is the basis for cell migration and phosphorylated filamin A stimulates the kinase activity of PAK1 and increases actin-regulating activity to facilitate cell motility. Tyrosyl phosphorylated PAK1 also stimulates invasion of breast cancer cells in response to PRL and three-dimensional (3D) collagen IV via transcription and secretion of MMP-1 and MMP-3 in a MAPK-dependent manner. These data illustrate the complex interaction between PRL and the cell microenvironment in breast cancer cells and suggest a pivotal role for PRL/PAK1 signaling in breast cancer metastasis.