Tumor suppressor Hippo/MST1 kinase mediates chemotaxis by regulating spreading and adhesion
Tumor suppressor Hippo/MST1 kinase mediates chemotaxis by regulating spreading and adhesion
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DOI：
10.1073/pnas.1211304109
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发表时间：
2012-08-21
影响因子：
11.1
通讯作者：
Devreotes, Peter N.
中科院分区：
文献类型：
--
作者：
Artemenko, Yulia;Batsios, Petros;Devreotes, Peter N.
趋化性依赖于一个平行通路网络，该网络协调细胞骨架事件以使细胞沿趋化梯度沿着移动。使用Dictyosteelium discoideum的正向遗传筛选，我们确定了Ste 20激酶KrsB，肿瘤抑制因子Hippo和MST 1/2的同源物，作为细胞扩散和底物附着的负调节因子。krsB（-）细胞的过度粘附降低了多细胞聚集的定向运动并延长了多细胞聚集的流动相。这些表型依赖于一个完整的激酶结构域和磷酸化的保守的苏氨酸（T176）内的激活环。化学引诱剂触发T176以异源三聚体G蛋白依赖性和PI 3 K-和TorC 2-独立的方式快速，瞬时自磷酸化。KrsB的活性磷酸化形式起到降低对基底的粘附的作用。总之，这些研究表明，KrsB的活性和非活性形式之间的循环可能提供适当的细胞迁移和趋化性所需的细胞粘附的动态调节。KrsB与另一个D. discoideum Hippo/MST同源物KrsA，但这两个基因在功能上不是冗余的。这些研究表明，Hippo/MST蛋白，如肿瘤抑制因子PTEN和癌基因Ras和PI 3 K，除了在调节细胞生长中发挥作用外，还在细胞形态学事件中发挥关键作用。
Chemotaxis depends on a network of parallel pathways that coordinate cytoskeletal events to bias cell movement along a chemoattractant gradient. Using a forward genetic screen in Dictyostelium discoideum, we identified the Ste20 kinase KrsB, a homolog of tumor suppressors Hippo and MST1/2, as a negative regulator of cell spreading and substrate attachment. The excessive adhesion of krsB(-) cells reduced directional movement and prolonged the streaming phase of multicellular aggregation. These phenotypes depended on an intact kinase domain and phosphorylation of a conserved threonine (T176) within the activation loop. Chemoattractants triggered a rapid, transient autophosphorylation of T176 in a heterotrimeric G protein-dependent and PI3K- and TorC2-independent manner. The active phosphorylated form of KrsB acts to decrease adhesion to the substrate. Taken together these studies suggest that cycling between active and inactive forms of KrsB may provide the dynamic regulation of cell adhesion needed for proper cell migration and chemotaxis. KrsB interacts genetically with another D. discoideum Hippo/MST homolog, KrsA, but the two genes are not functionally redundant. These studies show that Hippo/MST proteins, like the tumor suppressor PTEN and oncogenes Ras and PI3K, play a key role in cell morphological events in addition to their role in regulating cell growth.