c-Jun N-Terminal Kinase Phosphorylation of MARCKSL1 Determines Actin Stability and Migration in Neurons and in Cancer Cells
c-Jun N-Terminal Kinase Phosphorylation of MARCKSL1 Determines Actin Stability and Migration in Neurons and in Cancer Cells
复制标题
DOI：
10.1128/mcb.00713-12
复制
发表时间：
2012-09-01
影响因子：
5.3
通讯作者：
Coffey, Eleanor T.
中科院分区：
文献类型：
--
作者：
Bjorkblom, Benny;Padzik, Artur;Coffey, Eleanor T.
细胞迁移是一种基本的生物学功能，在发育和再生过程中至关重要，而失调的迁移则是神经出生缺陷和癌症转移的基础。 MARCKS 样蛋白 1 (MARCKSL1) 在神经组织中广泛表达，与 Jun N 末端蛋白激酶 (JNK) 一样，它是神经管形成所必需的，但其机制尚不清楚。在这里，我们表明 MARCKSL1 直接被 JNK 的 C 端残基（S120、T148 和 T183）磷酸化。这种磷酸化使 MARCKSL1 能够捆绑和稳定 F-肌动蛋白，增加丝足数量和动态，并延迟神经元的迁移。相反，当 MARCKSL1 磷酸化受到抑制时，肌动蛋白迁移率增加，丝状伪足形成受到损害，而片状伪足形成增强，细胞迁移也是如此。我们发现 MARCKSL1 mRNA 在多种癌症类型中上调，并且 MARCKSL1 蛋白在原发性前列腺癌中强烈诱导。前列腺癌细胞或神经元中的基因敲除揭示了 MARCKSL1 在依赖于磷酸化状态的迁移中的关键作用；磷酸模拟物 MARCKSL1 (MARCKSL1(S120D,T148D,T183D)) 抑制迁移，而去磷酸 MARCKSL(1S120A,T148A,T183A) 诱导迁移。总之，这些数据表明，MARCKSL1 的 JNK 磷酸化调节生理条件下的肌动蛋白稳态、丝状足和片状足的形成以及神经元迁移，并且当在前列腺癌细胞中异位表达时，MARCKSL1 再次决定细胞运动。
Cell migration is a fundamental biological function, critical during development and regeneration, whereas deregulated migration underlies neurological birth defects and cancer metastasis. MARCKS-like protein 1 (MARCKSL1) is widely expressed in nervous tissue, where, like Jun N-terminal protein kinase (JNK), it is required for neural tube formation, though the mechanism is unknown. Here we show that MARCKSL1 is directly phosphorylated by JNK on C-terminal residues (S120, T148, and T183). This phosphorylation enables MARCKSL1 to bundle and stabilize F-actin, increase filopodium numbers and dynamics, and retard migration in neurons. Conversely, when MARCKSL1 phosphorylation is inhibited, actin mobility increases and filopodium formation is compromised whereas lamellipodium formation is enhanced, as is cell migration. We find that MARCKSL1 mRNA is upregulated in a broad range of cancer types and that MARCKSL1 protein is strongly induced in primary prostate carcinomas. Gene knockdown in prostate cancer cells or in neurons reveals a critical role for MARCKSL1 in migration that is dependent on the phosphorylation state; phosphomimetic MARCKSL1 (MARCKSL1(S120D,T148D,T183D)) inhibits whereas dephospho-MARCKSL(1S120A,T148A,T183A) induces migration. In summary, these data show that JNK phosphorylation of MARCKSL1 regulates actin homeostasis, filopodium and lamellipodium formation, and neuronal migration under physiological conditions and that, when ectopically expressed in prostate cancer cells, MARCKSL1 again determines cell movement.