TY - JOUR
T1 - YAP and TAZ, hippo signaling targets, act as a rheostat for nuclear SHP2 function
AU - Tsutsumi, Ryouhei
AU - Masoudi, Mohammad
AU - Takahashi, Atsushi
AU - Fujii, Yumiko
AU - Hayashi, Takeru
AU - Kikuchi, Ippei
AU - Satou, Yumeko
AU - Taira, Masanori
AU - Hatakeyama, Masanori
N1 - Funding Information:
We thank H. Sasaki for plasmids and B. Neel for Ptpn11 fl/KO MEFs. This work was supported by Grants-in-Aid for Scientific Research on Innovative Area from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (to M.H.) and by the Uehara Memorial Foundation (to R.T.).
PY - 2013/9/30
Y1 - 2013/9/30
N2 - SHP2 is a ubiquitously expressed protein tyrosine phosphatase, deregulation of which is associated with malignant neoplasms and developmental disorders. SHP2 is required for full activation of RAS-Erk signaling in the cytoplasm and is also present in the nucleus, where it promotes Wnt target gene activation through dephosphorylation of parafibromin. SHP2 is distributed both to the cytoplasm and nucleus at low cell density but is excluded from the nucleus at high cell density. Here, we show that SHP2 physically interacts with transcriptional coactivators YAP and TAZ, targets of the cell-density-sensing Hippo signal. Through the interaction, nonphosphorylated YAP/TAZ promote nuclear translocalization of SHP2, which in turn stimulates TCF/LEF- and TEAD-regulated genes via parafibromin dephosphorylation. Conversely, YAP/TAZ phosphorylated by Hippo signaling sequester SHP2 in the cytoplasm, thereby preventing nuclear accumulation of SHP2. Hence, YAP/TAZ serve as a rheostat for nuclear SHP2 function, which is switched off by the Hippo signal.
AB - SHP2 is a ubiquitously expressed protein tyrosine phosphatase, deregulation of which is associated with malignant neoplasms and developmental disorders. SHP2 is required for full activation of RAS-Erk signaling in the cytoplasm and is also present in the nucleus, where it promotes Wnt target gene activation through dephosphorylation of parafibromin. SHP2 is distributed both to the cytoplasm and nucleus at low cell density but is excluded from the nucleus at high cell density. Here, we show that SHP2 physically interacts with transcriptional coactivators YAP and TAZ, targets of the cell-density-sensing Hippo signal. Through the interaction, nonphosphorylated YAP/TAZ promote nuclear translocalization of SHP2, which in turn stimulates TCF/LEF- and TEAD-regulated genes via parafibromin dephosphorylation. Conversely, YAP/TAZ phosphorylated by Hippo signaling sequester SHP2 in the cytoplasm, thereby preventing nuclear accumulation of SHP2. Hence, YAP/TAZ serve as a rheostat for nuclear SHP2 function, which is switched off by the Hippo signal.
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U2 - 10.1016/j.devcel.2013.08.013
DO - 10.1016/j.devcel.2013.08.013
M3 - Article
C2 - 24035415
AN - SCOPUS:84884722390
VL - 26
SP - 658
EP - 665
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
IS - 6
ER -