PAK1 regulates breast cancer cell invasion through secretion of matrix metalloproteinases in response to prolactin and three-dimensional collagen IV.
PAK1 regulates breast cancer cell invasion through secretion of matrix metalloproteinases in response to prolactin and three-dimensional collagen IV.
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DOI：
10.1210/me.2012-1322
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发表时间：
2013-06
影响因子：
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通讯作者：
Leah C. Rider;Peter O. Oladimeji;M. Diakonova
中科院分区：
文献类型：
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作者：
Leah C. Rider;Peter O. Oladimeji;M. Diakonova
p21 激活的丝氨酸-苏氨酸激酶 (PAK1) 与乳腺癌有关。我们之前已经证明，PAK1 是由催乳素 (PRL) 激活的 Janus 酪氨酸激酶 (JAK2) 酪氨酰磷酸化的。尽管 PRL 和 PAK1 在乳腺癌中的作用已得到广泛认可，但其机制仍知之甚少。在本研究中，PRL激活的PAK1通过Matrigel刺激TMX2-28人乳腺癌细胞的侵袭。三维 (3D) IV 型胶原蛋白刺激基质蛋白酶、金属蛋白酶 (MMP)-1 和 -3 的分泌，PAK1 的 PRL 依赖性酪氨酰磷酸化进一步增强这种分泌。 3D IV 型胶原蛋白还刺激 MMP-2 的表达和分泌，但与 MMP-1 和 -3 相比，PRL/PAK1 信号传导下调 MMP-2 的表达和分泌。相比之下，MMP-9 的表达和分泌受到 3D 胶原蛋白 I 的刺激，而不是胶原蛋白 IV 的刺激，并且不受 PRL 的影响，但会被 PAK1 下调。 MMP-1 和-3 是必需的，MMP-2 有助于PRL 依赖性入侵。 ERK1/2 信号传导似乎是 MMP-1 和 -3 表达和分泌增强以及 PRL 依赖性侵袭增强所必需的。 p38 MAPK 和 c-Jun N 末端激酶 1/2 通路参与 MMP-1 和 -3 的产生以及 PRL/PAK1 依赖性细胞侵袭。总之，这些数据说明了人乳腺癌细胞中基质与 PRL/PAK1 信号传导之间复杂的相互作用，并表明 PRL 依赖性 PAK1 酪氨酰磷酸化在 MMP 分泌中的关键作用。
p21-Activated serine-threonine kinase (PAK1) is implicated in breast cancer. We have shown previously that PAK1 is tyrosyl phosphorylated by prolactin (PRL)-activated Janus tyrosine kinase (JAK2). Although a role for both PRL and PAK1 in breast cancer is widely acknowledged, the mechanism remains poorly understood. In the present study, PRL-activated PAK1 stimulates the invasion of TMX2-28 human breast cancer cells through Matrigel. Three-dimensional (3D) collagen IV stimulates the secretion of the matrix proteases, metalloproteinase (MMP)-1 and -3 that is further enhanced by the PRL-dependent tyrosyl phosphorylation of PAK1. 3D collagen IV also stimulates the expression and secretion of MMP-2, but in contrast to MMP-1 and -3, PRL/PAK1 signaling down-regulates MMP-2 expression and secretion. In contrast, MMP-9 expression and secretion are stimulated by 3D collagen I, not collagen IV, and are not affected by PRL but are down-regulated by PAK1. MMP-1 and -3 are required and MMP-2 contributes to PRL-dependent invasion. ERK1/2 signaling appears to be required for the enhanced expression and secretion of MMP-1 and -3 and enhanced PRL-dependent invasion. p38 MAPK and c-Jun N-terminal kinase 1/2 pathways participate in production of MMP-1 and -3 as well as in PRL/PAK1-dependent cell invasion. Together, these data illustrate the complex interaction between the substratum and PRL/PAK1 signaling in human breast cancer cells and suggest a pivotal role for PRL-dependent PAK1 tyrosyl phosphorylation in MMP secretion.