title: Full activity of the deleted in liver cancer 1 (DLC1) tumor suppressor depends on an LD-like motif that binds talin and focal adhesion kinase (FAK).
abstract: The deleted in liver cancer 1 (DLC1) tumor suppressor gene, which is frequently inactivated in cancer, encodes a Rho-GAP (GTPase activating protein) focal adhesion protein whose negative regulation of Rho-GTPases is necessary but not sufficient for its full tumor suppressor activity. Here, we report that DLC1 forms a complex with two prooncogenic focal adhesion proteins, talin and the focal adhesion kinase (FAK). We identified an 8-aa sequence (residues 469LDDILYHV476) in DLC1 and designated it an LD-like motif, because it shares homology with the LD motifs of paxillin. This motif was necessary for DLC1 binding to talin and FAK, because a DLC1 mutant, from which six of the residues have been deleted, and another mutant carrying amino acid substitutions in three of the residues are deficient for binding both proteins and localization of DLC1 to focal adhesions. FAK binding was independent of talin and vice versa. In bioassays, both DLC1 mutants were less active than wild-type (WT) DLC1, although the ability of the mutants to negatively regulate overall Rho-GTP was not impaired. We conclude that the LD-like motif, which binds talin and FAK, is required for the full tumor suppressor activity of DLC1 and contributes to the association of DLC1 with focal adhesions.
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Guorong
authors.initials: G
authors.lastname: Li
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Du
authors.forename: William C
authors.initials: WC
authors.lastname: Vass
authors.forename: Alex G
authors.initials: AG
authors.lastname: Papageorge
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Lowy
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Qian
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D041681:NIH 3T3 Cells; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D016608:Talin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000070876:Tensins; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D016608:Talin; D000070876:Tensins; D025521:Tumor Suppressor Proteins; C085379:rho GTPase-activating protein; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human