Src kinase phosphorylates RUNX3 at tyrosine residues and localizes the protein in the cytoplasm.
RUNX3 is a transcription factor that functions as a tumor suppressor. In some cancers, RUNX3 expression is down-regulated, usually due to promoter hypermethylation. Recently, it was found that RUNX3 can also be inactivated by the mislocalization of the protein in the cytoplasm. The molecular mechanisms controlling this mislocalization are poorly understood. In this study, we found that the overexpression of Src results in the tyrosine phosphorylation and cytoplasmic localization of RUNX3. We also found that the tyrosine residues of endogenous RUNX3 are phosphorylated and that the protein is localized in the cytoplasm in Src-activated cancer cell lines. We further showed that the knockdown of Src by small interfering RNA, or the inhibition of Src kinase activity by a chemical inhibitor, causes the re-localization of RUNX3 to the nucleus. Collectively, our results demonstrate that the tyrosine phosphorylation of RUNX3 by activated Src is associated with the cytoplasmic localization of RUNX3 in gastric and breast cancers.
Goh
Yun-Mi
YM
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Cinghu
Senthilkumar
S
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Hong
Eileen Tan Hwee
ETH
Cancer Science Institute Singapore, National University of Singapore and Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
Lee
You-Soub
YS
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Kim
Jang-Hyun
JH
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Jang
Ju-Won
JW
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Li
Ying-Hui
YH
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Chi
Xin-Zi
XZ
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Lee
Kyeong-Sook
KS
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Wee
Heejun
H
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Ito
Yoshiaki
Y
Cancer Science Institute Singapore, National University of Singapore and Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
Oh
Byung-Chul
BC
Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-ku, Inchon 406-840, South Korea. Electronic address: bcoh@gachon.ac.kr.
Bae
Suk-Chul
SC
Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea. Electronic address: scbae@chungbuk.ac.kr.
D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D050677:Core Binding Factor Alpha 3 Subunit / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D050677:Core Binding Factor Alpha 3 Subunit; D034741:RNA, Small Interfering; C493729:Runx3 protein, human; D014443:Tyrosine; D019061:src-Family Kinases