title: Promotion of colorectal cancer invasion and metastasis through activation of NOTCH-DAB1-ABL-RHOGEF protein TRIO.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sonoshita
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Itatani
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kakizaki
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Department of Physiology and Cell Biology, Division of Anatomy and Neurobiology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Terashima
authors.affiliation: Division of Developmental Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Katsuyama
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. taketo@mfour.med.kyoto-u.ac.jp.
authors.forename: M Mark
authors.initials: MM
authors.lastname: Taketo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C115785:DAB1 protein, human; C103773:Dab1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D051880:Receptors, Notch; D064067:Rho Guanine Nucleotide Exchange Factors; C490975:Trio protein, mouse; D017346:Protein Serine-Threonine Kinases; C099628:TRIO protein, human