title: Identification of serum-derived sphingosine-1-phosphate as a small molecule regulator of YAP.
abstract: Hippo signaling represents a tumor suppressor pathway that regulates organ size and tumorigenesis through phosphorylation and inhibition of the transcription coactivator YAP. Here, we show that serum deprivation dramatically induces YAP Ser127 phosphorylation and cytoplasmic retention, independent of cell-cell contact. Through chemical isolation and activity profiling, we identified serum-derived sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) as small molecule activators of YAP. S1P induces YAP nuclear localization through S1P(2) receptor, Rho GTPase activation, and F-actin polymerization, independent of the core Hippo pathway kinases. Bioinformatics studies also showed that S1P stimulation induces YAP target gene expression in mouse liver and human embryonic stem cells. These results revealed potent small molecule regulators of YAP and suggest that S1P and LPA might modulate cell proliferation and tumorigenesis through YAP activation.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Miller
authors.forename: Jiayi
authors.initials: J
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: DeRan
authors.forename: Chunlei
authors.initials: C
authors.lastname: Wu
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Su
authors.forename: Ghislain M C
authors.initials: GM
authors.lastname: Bonamy
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peters
authors.forename: Xu
authors.initials: X
authors.lastname: Wu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000097:blood / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D018797:Cell Cycle Proteins; D008246:Lysophospholipids; D009687:Nuclear Proteins; D049349:Receptors, Lysosphingolipid; D014157:Transcription Factors; C456659:YY1AP1 protein, human; C060506:sphingosine 1-phosphate; D020741:rho GTP-Binding Proteins; D013110:Sphingosine; C032881:lysophosphatidic acid