Promotion of Colorectal Cancer Invasion and Metastasis through Activation of NOTCH–DAB1–ABL–RHOGEF Protein TRIO

Abstract

We have recently identifi ed 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 signifi cantly 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][199][200][201][202][203][204][205][206][207][208][209][210][211]

The Abl pathway bifurcates to balance Enabled and Rac signaling in axon patterning in Drosophila

“…Together, these interactions allow the Abl signaling network to control a wide variety of axon patterning decisions throughout animal phylogeny, perhaps by coordinating the Ena-dependent dynamics of linear actin bundles with the WAVE-dependent dynamics of branched actin networks. The relationship of Dab to Abl has long been controversial (Gertler et al, 1993;Howell et al, 1997;Liebl et al, 2003;Song et al, 2010;Sonoshita et al, 2015). For some time, it was unclear whether Dab is even a core component of the Abl pathway, although more recently we established the central role of Dab in Abl pathway function (Liebl et al, 2003;Song et al, 2010).…”

“…2A,B It has been suggested that the Abl and Dab orthologs associate in mammalian cells (Sonoshita et al, 2015). We therefore tested Abl/ Dab association in Drosophila by co-immunoprecipitation (co-IP) from embryo extracts and found that immunoprecipitation of Abl co-precipitated Dab (Fig.…”

“…Nearly every component has been linked, genetically, biochemically or both, to nearly every other component (Forsthoefel et al, 2005;Gertler et al, 1993;Hill et al, 1995;Liebl et al, 2000;Sonoshita et al, 2015). Many experiments have yielded contradictory pictures of the relationships among Abl signaling components and of their roles in motility (Bashaw et al, 2000;Bear et al, 2000;Forsthoefel et al, 2005;Hsouna et al, 2003;Juang and Hoffmann, 1999;Krause et al, 2002;Liebl et al, 2003;Lin et al, 2009;Song et al, 2010;Trichet et al, 2008;Wills et al, 1999a,b).…”

Multifunctional Abl kinases in health and disease

“…Furthermore, Abl kinases promote the expression and/or localization of other proteins that regulate cell invasion, such as the type 1-matrix metalloproteinase MT1-MMP (also known as MMP14) (Chevalier et al, 2015;Mader et al, 2011;Smith-Pearson et al, 2010). A recent report demonstrated a so-far-unknown role for Abl kinases in promoting the invasion and metastasis of colorectal cancer cells, by linking the activation of NOTCH to the phosphorylation of TRIO, which enhances its Rho-GEF activity, leading to a corresponding increase of Rho-GTP levels (Sonoshita et al, 2015) (see poster).…”

New perspectives on the roles of Abl tyrosine kinase in axon patterning

“…Indeed, in mammalian cells it is known that Abl and Src phosphorylate tyrosine residues in the C-terminal portion of Trio to stimulate its Rho GEF activity. 40 The Trio domain that is phosphorylated in that model, however, is not conserved in the fly protein, ruling it out as the mechanism of Rac GEF activation in our experiments. Previous studies showed in vitro binding of purified Drosophila Abl and Trio fragments from cells, and overexpression of Abl was capable of increasing Trio phosphorylation.…”