title: Epidermal growth factor activates the Rho GTPase-activating protein (GAP) Deleted in Liver Cancer 1 via focal adhesion kinase and protein phosphatase 2A.
abstract: Deleted in Liver Cancer 1 (DLC1) is a RHO GTPase-activating protein (GAP) that negatively regulates RHO. Through its GAP activity, it modulates the actin cytoskeleton network and focal adhesion dynamics, ultimately leading to suppression of cell invasion and metastasis. Despite its presence in various structural and signaling components, little is known about how the activity of DLC1 is regulated at focal adhesions. Here we show that EGF stimulation activates the GAP activity of DLC1 through a concerted mechanism involving DLC1 phosphorylation by MEK/ERK and its subsequent dephosphorylation by protein phosphatase 2A (PP2A) and inhibition of focal adhesion kinase by MEK/ERK to allow the binding between DLC1 and PP2A. Phosphoproteomics and mutation studies revealed that threonine 301 and serine 308 on DLC1, known previously to be mutated in certain cancers, are required for DLC1-PP2A interaction and the subsequent activation of DLC1 upon their dephosphorylation. The intricate interplay of this "MEK/ERK-focal adhesion kinase-DLC1-PP2A" quartet provides a novel checkpoint in the spatiotemporal control of cell spreading and cell motility.
authors.affiliation: From the Cell Signaling and Developmental Biology Laboratory, Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543 Singapore and the Mechanobiology Institute, National University of Singapore, 5A Engineering Drive, 117411 Singapore.
authors.forename: Archna
authors.initials: A
authors.lastname: Ravi
authors.affiliation: From the Cell Signaling and Developmental Biology Laboratory, Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543 Singapore and the Mechanobiology Institute, National University of Singapore, 5A Engineering Drive, 117411 Singapore.
authors.forename: Shelly
authors.initials: S
authors.lastname: Kaushik
authors.affiliation: the Mechanobiology Institute, National University of Singapore, 5A Engineering Drive, 117411 Singapore.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Ravichandran
authors.affiliation: the Mechanobiology Institute, National University of Singapore, 5A Engineering Drive, 117411 Singapore.
authors.forename: Catherine Qiurong
authors.initials: CQ
authors.lastname: Pan
authors.affiliation: From the Cell Signaling and Developmental Biology Laboratory, Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543 Singapore and the Mechanobiology Institute, National University of Singapore, 5A Engineering Drive, 117411 Singapore dbslowbc@nus.edu.sg.
authors.forename: Boon Chuan
authors.initials: BC
authors.lastname: Low
mesh_terms: D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D022001:Focal Adhesions / Q000187:drug effects*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D020543:Proteome / Q000032:analysis; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014945:Wound Healing
chemical_list: C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D020543:Proteome; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D054648:Protein Phosphatase 2
keywords: Deleted In Liver Cancer 1 (DLC1); Focal Adhesion Kinase (FAK); GTPase-activating Protein (GAP); MEK/ERK; PTK2 Protein-tyrosine Kinase 2 (PTK2); Phosphorylation; Protein Phosphatase 2 (PP2A)