TY - JOUR
T1 - Endosomal phosphatidylserine is critical for the YAP signalling pathway in proliferating cells
AU - Matsudaira, Tatsuyuki
AU - Mukai, Kojiro
AU - Noguchi, Taishin
AU - Hasegawa, Junya
AU - Hatta, Tomohisa
AU - Iemura, Shun Ichiro
AU - Natsume, Tohru
AU - Miyamura, Norio
AU - Nishina, Hiroshi
AU - Nakayama, Jun
AU - Semba, Kentaro
AU - Tomita, Takuya
AU - Murata, Shigeo
AU - Arai, Hiroyuki
AU - Taguchi, Tomohiko
N1 - Funding Information:
We thank J. McKenzie (Lawrence Berkeley National Laboratory) for comments on the manuscript and C. Inoue (the University of Tokyo) for her assistance. This work was supported by JSPS KAKENHI Grant Numbers JP16H04782 (To.T.), JP15H05903 (To.T.), JP17H06164 (H.A.), JP17H06418 (H.A.), and JP17K15445 (K.M.); AMED-CREST (15652265) (H.A.); the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries and Food Industry from the Ministry of Agriculture, Forestry and Fisheries of Japan (15650430) (H.A.); a Grant-in-Aid from the Uehara Memorial Foundation (H.N.); JSPS Research Fellowship for Young Scientists (DC1, 12380) (T.M.); and Ono Pharmaceutical Co., Ltd. (H.A.).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Yes-associated protein (YAP) is a recently discovered growth-promoting transcription coactivator that has been shown to regulate the malignancy of various cancers. How YAP is regulated is not fully understood. Here, we show that one of the factors regulating YAP is phosphatidylserine (PS) in recycling endosomes (REs). We use proximity biotinylation to find proteins proximal to PS. Among these proteins are YAP and multiple proteins related to YAP signalling. Knockdown of ATP8A1 (an RE PS-flippase) or evectin-2 (an RE-resident protein) and masking of PS in the cytoplasmic leaflet of membranes, all suppress nuclear localization of YAP and YAP-dependent transcription. ATP8A1 knockdown increases the phosphorylated (activated) form of Lats1 that phosphorylates and inactivates YAP, whereas evectin-2 knockdown reduces the ubiquitination and increased the level of Lats1. The proliferation of YAP-dependent metastatic cancer cells is suppressed by knockdown of ATP8A1 or evectin-2. These results suggest a link between a membrane phospholipid and cell proliferation.
AB - Yes-associated protein (YAP) is a recently discovered growth-promoting transcription coactivator that has been shown to regulate the malignancy of various cancers. How YAP is regulated is not fully understood. Here, we show that one of the factors regulating YAP is phosphatidylserine (PS) in recycling endosomes (REs). We use proximity biotinylation to find proteins proximal to PS. Among these proteins are YAP and multiple proteins related to YAP signalling. Knockdown of ATP8A1 (an RE PS-flippase) or evectin-2 (an RE-resident protein) and masking of PS in the cytoplasmic leaflet of membranes, all suppress nuclear localization of YAP and YAP-dependent transcription. ATP8A1 knockdown increases the phosphorylated (activated) form of Lats1 that phosphorylates and inactivates YAP, whereas evectin-2 knockdown reduces the ubiquitination and increased the level of Lats1. The proliferation of YAP-dependent metastatic cancer cells is suppressed by knockdown of ATP8A1 or evectin-2. These results suggest a link between a membrane phospholipid and cell proliferation.
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U2 - 10.1038/s41467-017-01255-3
DO - 10.1038/s41467-017-01255-3
M3 - Article
C2 - 29093443
AN - SCOPUS:85032995033
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1246
ER -