NOS1AP Functionally Associates with YAP To Regulate Hippo Signaling.
Deregulation of cellular polarity proteins and their associated complexes leads to changes in cell migration and proliferation. The nitric oxide synthase 1 adaptor protein (NOS1AP) associates with the tumor suppressor protein Scribble to control cell migration and oncogenic transformation. However, how NOS1AP is linked to the cell signaling events that curb oncogenic progression has remained elusive. Here we identify several novel NOS1AP isoforms, NOS1APd, NOS1APe, and NOS1APf, with distinct cellular localizations. We show that isoforms with a membrane-interacting phosphotyrosine binding (PTB) domain can associate with Scribble and recognize acidic phospholipids. In a screen to identify novel binding proteins, we have discovered a complex consisting of NOS1AP and the transcriptional coactivator YAP linking NOS1AP to the Hippo signaling pathway. Silencing of NOS1AP reduces the phosphorylation of YAP and of the upstream kinase Lats1. Conversely, expression of NOS1AP promotes YAP and Lats1 phosphorylation, which correlates with reduced TEAD activity and restricted cell proliferation. Together, these data implicate a role for NOS1AP in the regulation of core Hippo signaling and are consistent with the idea that NOS1AP functions as a tumor suppressor.
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Leanne
L
Clattenburg
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Michael
M
Wigerius
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Jiansong
J
Qi
Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
Jan K
JK
Rainey
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Jillian L
JL
Rourke
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Shanmugam
S
Muruganandan
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Christopher J
CJ
Sinal
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada Department of Surgery, Dalhousie University, Halifax, NS, Canada jim.fawcett@dal.ca.
James P
JP
Fawcett
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000032:analysis / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C488082:NOS1AP protein, rat; D020033:Protein Isoforms; D000091102:YAP-Signaling Proteins; C509425:Yap1 protein, rat; D017346:Protein Serine-Threonine Kinases