TY - JOUR
T1 - Transglutaminase-mediated cross-linking of WDR54 regulates EGF receptor-signaling
AU - Maeda, Akane
AU - Nishino, Tasuku
AU - Matsuzaki, Ryota
AU - Yokoyama, Atsushi
AU - Suga, Hiroshi
AU - Yagi, Toshiki
AU - Konishi, Hiroaki
N1 - Funding Information:
This work was supported in part by Grants-in-Aid for Scientific Research and by the Knowledge Cluster Initiative from the Ministry of Education, Culture, Sports, Science and Technology , Japan ( 17K07341 ).
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2019/2
Y1 - 2019/2
N2 - WDR54 is a member of the WD40 repeat (WDR) domain-containing protein family that was recently identified as a novel oncogene in colorectal cancer. However, the molecular mechanism of WDR54 and its functional association with other molecules related to tumor cell growth are unknown. Here, we show that WDR54 can be cross-linked by the action of transglutaminase (TG) 2, which enhances the activation of EGF receptor-mediated signaling pathway. The most carboxyl-terminal WD domain was required for cross-linking. In addition, lysine 280 in WDR54, also in this WD domain, was an important residue for both cross-linking and ubiquitination. Cross-linked WDR54 was found in vesicles aggregated at the plasma membrane. The activated EGF receptor was co-localized with this vesicle, and the internalization of the EGF receptor into the cytosol was sustained. As a result, Erk activity in response to EGF stimulation was enhanced. Furthermore, the growth of the cells lacking WDR54 expression generated by genome editing was delayed compared with that in wild-type cells. Because TG2 is also has been proposed to activate the EGF receptor-signaling and proliferation of tumor cells, WDR54 might have a functional relationship with the EGF receptor and TG2. Our study on the mechanism of biological function of WDR54 may provide rationale for the design and development of a cancer drug based on inhibiting the post-translational modification of this oncogene product.
AB - WDR54 is a member of the WD40 repeat (WDR) domain-containing protein family that was recently identified as a novel oncogene in colorectal cancer. However, the molecular mechanism of WDR54 and its functional association with other molecules related to tumor cell growth are unknown. Here, we show that WDR54 can be cross-linked by the action of transglutaminase (TG) 2, which enhances the activation of EGF receptor-mediated signaling pathway. The most carboxyl-terminal WD domain was required for cross-linking. In addition, lysine 280 in WDR54, also in this WD domain, was an important residue for both cross-linking and ubiquitination. Cross-linked WDR54 was found in vesicles aggregated at the plasma membrane. The activated EGF receptor was co-localized with this vesicle, and the internalization of the EGF receptor into the cytosol was sustained. As a result, Erk activity in response to EGF stimulation was enhanced. Furthermore, the growth of the cells lacking WDR54 expression generated by genome editing was delayed compared with that in wild-type cells. Because TG2 is also has been proposed to activate the EGF receptor-signaling and proliferation of tumor cells, WDR54 might have a functional relationship with the EGF receptor and TG2. Our study on the mechanism of biological function of WDR54 may provide rationale for the design and development of a cancer drug based on inhibiting the post-translational modification of this oncogene product.
KW - Cross-linking
KW - ERK
KW - Epidermal growth factor receptor (egfr)
KW - Ubiquitination
KW - WD40 repeat
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U2 - 10.1016/j.bbamcr.2018.11.009
DO - 10.1016/j.bbamcr.2018.11.009
M3 - Article
C2 - 30458214
AN - SCOPUS:85057298353
SN - 0167-4889
VL - 1866
SP - 285
EP - 295
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 2
ER -
