TY - JOUR
T1 - RUNX2 Phosphorylation by Tyrosine Kinase ABL Promotes Breast Cancer Invasion
AU - He, Fang
AU - Matsumoto, Yoshinori
AU - Asano, Yosuke
AU - Yamamura, Yuriko
AU - Katsuyama, Takayuki
AU - La Rose, Jose
AU - Tomonobu, Nahoko
AU - Komalasari, Ni Luh Gede Yoni
AU - Sakaguchi, Masakiyo
AU - Rottapel, Robert
AU - Wada, Jun
N1 - Funding Information:
This work was supported by a grant from the Japan Society for the Promotion of Science, the Princess Takamatsu Cancer Research Fund, the Kobayashi Foundation, the Okinaka Memorial Institute for Medical Research and the Ryobi Teien Memory Foundation. FH is supported by a scholarship to overseas students funded by the Uehara Memorial Foundation.
Publisher Copyright:
© Copyright © 2021 He, Matsumoto, Asano, Yamamura, Katsuyama, La Rose, Tomonobu, Komalasari, Sakaguchi, Rottapel and Wada.
PY - 2021/5/31
Y1 - 2021/5/31
N2 - Activity of transcription factors is normally regulated through interaction with other transcription factors, chromatin remodeling proteins and transcriptional co-activators. In distinction to these well-established transcriptional controls of gene expression, we have uncovered a unique activation model of transcription factors between tyrosine kinase ABL and RUNX2, an osteoblastic master transcription factor, for cancer invasion. We show that ABL directly binds to, phosphorylates, and activates RUNX2 through its SH2 domain in a kinase activity-dependent manner and that the complex formation of these proteins is required for expression of its target gene MMP13. Additionally, we show that the RUNX2 transcriptional activity is dependent on the number of its tyrosine residues that are phosphorylated by ABL. In addition to regulation of RUNX2 activity, we show that ABL transcriptionally enhances RUNX2 expression through activation of the bone morphogenetic protein (BMP)-SMAD pathway. Lastly, we show that ABL expression in highly metastatic breast cancer MDA-MB231 cells is associated with their invasive capacity and that ABL-mediated invasion is abolished by depletion of endogenous RUNX2 or MMP13. Our genetic and biochemical evidence obtained in this study contributes to a mechanistic insight linking ABL-mediated phosphorylation and activation of RUNX2 to induction of MMP13, which underlies a fundamental invasive capacity in cancer and is different from the previously described model of transcriptional activation.
AB - Activity of transcription factors is normally regulated through interaction with other transcription factors, chromatin remodeling proteins and transcriptional co-activators. In distinction to these well-established transcriptional controls of gene expression, we have uncovered a unique activation model of transcription factors between tyrosine kinase ABL and RUNX2, an osteoblastic master transcription factor, for cancer invasion. We show that ABL directly binds to, phosphorylates, and activates RUNX2 through its SH2 domain in a kinase activity-dependent manner and that the complex formation of these proteins is required for expression of its target gene MMP13. Additionally, we show that the RUNX2 transcriptional activity is dependent on the number of its tyrosine residues that are phosphorylated by ABL. In addition to regulation of RUNX2 activity, we show that ABL transcriptionally enhances RUNX2 expression through activation of the bone morphogenetic protein (BMP)-SMAD pathway. Lastly, we show that ABL expression in highly metastatic breast cancer MDA-MB231 cells is associated with their invasive capacity and that ABL-mediated invasion is abolished by depletion of endogenous RUNX2 or MMP13. Our genetic and biochemical evidence obtained in this study contributes to a mechanistic insight linking ABL-mediated phosphorylation and activation of RUNX2 to induction of MMP13, which underlies a fundamental invasive capacity in cancer and is different from the previously described model of transcriptional activation.
KW - ABL - Abelson murine leukemia viral oncogene homolog
KW - Runx2 (runt-related transcription factor 2)
KW - invasion
KW - phosphorylation
KW - tyrosine
UR - http://www.scopus.com/inward/record.url?scp=85107835869&partnerID=8YFLogxK
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U2 - 10.3389/fonc.2021.665273
DO - 10.3389/fonc.2021.665273
M3 - Article
AN - SCOPUS:85107835869
VL - 11
JO - Frontiers in Oncology
JF - Frontiers in Oncology
SN - 2234-943X
M1 - 665273
ER -