title: TGF-β/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis.
abstract: The mechanisms by which TGF-β promotes lung adenocarcinoma (ADC) metastasis are largely unknown. Here, we report that in lung ADC cells, TGF-β potently induces expression of DOCK4, but not other DOCK family members, via the Smad pathway and that DOCK4 induction mediates TGF-β's prometastatic effects by enhancing tumor cell extravasation. TGF-β-induced DOCK4 stimulates lung ADC cell protrusion, motility, and invasion without affecting epithelial-to-mesenchymal transition. These processes, which are fundamental to tumor cell extravasation, are driven by DOCK4-mediated Rac1 activation, unveiling a novel link between TGF-β and Rac1. Thus, our findings uncover the atypical Rac1 activator DOCK4 as a key component of the TGF-β/Smad pathway that promotes lung ADC cell extravasation and metastasis.
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA; Graduate Program in Genetics, Stony Brook University, Stony Brook, New York 11794, USA;
authors: Jia-Ray
authors: JR
authors: Yu
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors: Yilin
authors: Y
authors: Tai
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors: Ying
authors: Y
authors: Jin
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors: Molly C
authors: MC
authors: Hammell
authors: Unit for Laboratory Animal Medicine, Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: J Erby
authors: JE
authors: Wilkinson
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors: Jae-Seok
authors: JS
authors: Roe
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors: Christopher R
authors: CR
authors: Vakoc
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;
authors: Linda
authors: L
authors: Van Aelst
mesh_terms: D000230:Adenocarcinoma / Q000503:physiopathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000503:physiopathology*; D051379:Mice; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C510122:DOCK4 protein, human; D020690:GTPase-Activating Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta
keywords: DOCK180 proteins; Rac1; TGF-β signaling; cell motility; lung adenocarcinoma metastasis; tumor cell extravasation
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