title: LIMD2 is a small LIM-only protein overexpressed in metastatic lesions that regulates cell motility and tumor progression by directly binding to and activating the integrin-linked kinase.
abstract: Proteins that communicate signals from the cytoskeleton to the nucleus are prime targets for effectors of metastasis as they often transduce signals regulating adhesion, motility, and invasiveness. LIM domain proteins shuttle between the cytoplasm and the nucleus, and bind to partners in both compartments, often coupling changes in gene expression to extracellular cues. In this work, we characterize LIMD2, a mechanistically undefined LIM-only protein originally found to be overexpressed in metastatic lesions but absent in the matched primary tumor. LIMD2 levels in fresh and archival tumors positively correlate with cell motility, metastatic potential, and grade, including bladder, melanoma, breast, and thyroid tumors. LIMD2 directly contributes to these cellular phenotypes as shown by overexpression, knockdown, and reconstitution experiments in cell culture models. The solution structure of LIMD2 that was determined using nuclear magnetic resonance revealed a classic LIM-domain structure that was highly related to LIM1 of PINCH1, a core component of the integrin-linked kinase-parvin-pinch complex. Structural and biochemical analyses revealed that LIMD2 bound directly to the kinase domain of integrin-linked kinase (ILK) near the active site and strongly activated ILK kinase activity. Cells that were null for ILK failed to respond to the induction of invasion by LIMD2. This strongly suggests that LIMD2 potentiates its biologic effects through direct interactions with ILK, a signal transduction pathway firmly linked to cell motility and invasion. In summary, LIMD2 is a new component of the signal transduction cascade that links integrin-mediated signaling to cell motility/metastatic behavior and may be a promising target for controlling tumor spread.
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Hongzhuang
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Pathology and Cell Biology, University of Montreal, Institute for Research in Immunology and Cancer.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Talebzadeh-Farrooji
authors.affiliation: Department of Pathology and Cell Biology, University of Montreal, Institute for Research in Immunology and Cancer.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Osborne
authors.affiliation: University of Akron, Akron, Ohio.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Prokop
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: McDonald
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Jayashree
authors.initials: J
authors.lastname: Karar
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Mei
authors.initials: M
authors.lastname: He
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
authors.affiliation: Aarhus University Hospital at Skejby Sygehus, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Orntoft
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Caton
authors.affiliation: Department of Surgery, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: William
authors.initials: W
authors.lastname: Fredericks
authors.affiliation: Department of Surgery, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Bruce
authors.initials: B
authors.lastname: Malkowicz
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Paterno
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Carolin
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: David W
authors.initials: DW
authors.lastname: Speicher
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Skordalakes
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Qihong
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
authors.affiliation: Department of Pathology and Cell Biology, University of Montreal, Institute for Research in Immunology and Cancer.
authors.forename: Katherine L B
authors.initials: KLB
authors.lastname: Borden
authors.affiliation: The Wistar Institute, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Rauscher
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D018450:Disease Progression; D005347:Fibroblasts / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000099200:Scaffold Protein ILK
chemical_list: D060588:LIM Domain Proteins; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK