Year: 2022
Type: article
Abstract: 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.
Source: Science Advances
Institutions: University of Miami, University of California San Diego, Sylvester Comprehensive Cancer Center, Moores Cancer Center, Ludwig Cancer Research, Sichuan University, State Key Laboratory of Oral Diseases, Cleveland Clinic, Duke University, Duke Medical Center, The University of Texas MD Anderson Cancer Center, Herbert Irving Comprehensive Cancer Center, Columbia University
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: Therapeutic efficacy of the CRL inhibitor MLN4924 in NF2 mutant mesothelioma, Protein phosphorylation and growth factor function, The mTOR and Hippo pathway in cell growth and cancer, Biomaterial Mimicry of Dynamic Matrix Stiffening During Tumor Progression, Developing Adhesome Technology as a Physical Marker of Highly Metastatic Cells, Mechanisms governing metastatic dormancy and reactivation, Collaborative Research: Heterogeneous Cancer Cell Mechanics Differentially Drives Mechanosensing and Migration, Contemporary Approaches to Cancer Cell Signaling and Communication, Cancer Center Support Grant (CCSG), Roles of mechanotransduction in organ regeneration and fibrosis, Functional interplay between Hippo and estrogen receptor ESR1
OpenAlex ID: W4281488186