机构：[1]Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.[2]Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.[3]Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.[4]Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.[5]Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.[6]Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.[7]State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.[8]Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH 44195, USA.[9]Regeneration Next Initiative, Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA.[10]Department of Cancer Biology and David H. Koch Center for Applied Research of GU Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.[11]Herbert Irving Comprehensive Cancer Center and Department of Genetics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10033, USA.
Semaphorins were originally identified as axonal guidance molecules, but they also control processes such as vascular development and tumorigenesis. The downstream signaling cascades of Semaphorins in these biological processes remain unclear. Here, we show that the class 3 Semaphorins (SEMA3s) activate the Hippo pathway to attenuate tissue growth, angiogenesis, and tumorigenesis. SEMA3B restoration in lung cancer cells with SEMA3B loss of heterozygosity suppresses cancer cell growth via activating the core Hippo kinases LATS1/2 (large tumor suppressor kinase 1/2). Furthermore, SEMA3 also acts through LATS1/2 to inhibit angiogenesis. We identified p190RhoGAPs as essential partners of the SEMA3A receptor PlexinA in Hippo regulation. Upon SEMA3 treatment, PlexinA interacts with the pseudo-guanosine triphosphatase (GTPase) domain of p190RhoGAP and simultaneously recruits RND GTPases to activate p190RhoGAP, which then stimulates LATS1/2. Disease-associated etiological factors, such as genetic lesions and oscillatory shear, diminish Hippo pathway regulation by SEMA3. Our study thus discovers a critical role of Hippo signaling in mediating SEMA3 physiological function.
基金：
Z.M. is supported by the National Institute of General Medical
Sciences of the National Institutes of Health (NIH) under award number R35GM142504. This
project is also, in part, supported by a grant from the Elsa U. Pardee Foundation to Z.M. K.-L.G.
is supported by NIH grants R35CA196878, R01CA268179, and R01GM51586. F.G.G. is
supported by NIH R01 CA191222 and R35 CA197566. A.J.E. is supported by NIH grants
R01CA206880 and R21CA217735 and National Science Foundation grant 1763139. B.Y. is
supported by an NIH training grant T32CA009523
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外文
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第一作者：
第一作者机构：[1]Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.[2]Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.[3]Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.[2]Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.[3]Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
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