Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) constitute a mammalian STE20-like serine/threonine kinase subfamily. Recent studies provide substantial evidence for MAP4K family kinases in the Hippo pathway regulation, suggesting a broad role of MAP4Ks in human physiology and diseases. However, a comprehensive analysis of the regulators and effectors for this key kinase family has not been fully achieved. Using a proteomic approach, we define the protein-protein interaction network for human MAP4K family kinases and reveal diverse cellular signaling events involving this important kinase family. Through it, we identify a STRIPAK complex component, STRN4, as a generic binding partner for MAP4Ks and a key regulator of the Hippo pathway in endometrial cancer development. Taken together, the results of our study not only generate a rich resource for further characterizing human MAP4K family kinases in numerous biological processes but also dissect the STRIPAK-mediated regulation of MAP4Ks in the Hippo pathway.

丝裂原活化的蛋白激酶激酶激酶激酶（MAP4Ks）构成哺乳动物的STE20样丝氨酸/苏氨酸激酶亚家族。最近的研究为MAP4K家族激酶在Hippo通路调控中提供了大量证据，表明MAP4K在人类生理和疾病中的广泛作用。但是，尚未完全实现对该关键激酶家族的调节子和效应子的全面分析。使用蛋白质组学的方法，我们定义了人MAP4K家族激酶的蛋白质-蛋白质相互作用网络，并揭示了涉及此重要激酶家族的各种细胞信号事件。通过它，我们确定了STRIPAK复合物成分STRN4，作为MAP4Ks的通用结合伴侣，是子宫内膜癌发展过程中Hippo通路的关键调节因子。在一起