American Association for Cancer Research
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Supplementary Figure S1 from Promotion of Colorectal Cancer Invasion and Metastasis through Activation of NOTCH–DAB1–ABL–RHOGEF Protein TRIO

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journal contribution
posted on 2023-04-03, 20:42 authored by Masahiro Sonoshita, Yoshiro Itatani, Fumihiko Kakizaki, Kenji Sakimura, Toshio Terashima, Yu Katsuyama, Yoshiharu Sakai, M. Mark Taketo

Supplementary Fig. S1 shows Dab1 expression in mouse intestinal tumors and in human CRC cell lines.



We have recently identified a metastasis suppressor gene for colorectal cancer: AES/Aes, which encodes an endogenous inhibitor of NOTCH signaling. When Aes is knocked out in the adenomatous epithelium of intestinal polyposis mice, their tumors become malignant, showing marked submucosal invasion and intravasation. Here, we show that one of the genes induced by NOTCH signaling in colorectal cancer is DAB1/Dab1. Genetic depletion of DAB1 suppresses cancer invasion and metastasis in the NOTCH signaling–activated mice. DAB1 is phosphorylated by ABL tyrosine kinase, which activates ABL reciprocally. Consistently, inhibition of ABL suppresses cancer invasion in mice. Furthermore, we show that one of the targets of ABL is the RAC/RHOGEF protein TRIO, and that phosphorylation at its Tyr residue 2681 (pY2681) causes RHO activation in colorectal cancer cells. Its unphosphorylatable mutation TRIO Y2681F reduces RHOGEF activity and inhibits invasion of colorectal cancer cells. Importantly, TRIO pY2681 correlates with significantly poorer prognosis of patients with colorectal cancer after surgery.Significance: These results indicate that TRIO pY2681 is one of the downstream effectors of NOTCH signaling activation in colorectal cancer, and can be a prognostic marker, helping to determine the therapeutic modality of patients with colorectal cancer. Cancer Discov; 5(2); 198–211. ©2014 AACR.See related commentary by Kranenburg, p. 115This article is highlighted in the In This Issue feature, p. 97

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