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.

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.
AuthorsHongzhuang Peng, Mehdi Talebzadeh-Farrooji, Michael J Osborne, Jeremy W Prokop, Paul C McDonald, Jayashree Karar, Zhaoyuan Hou, Mei He, Electron Kebebew, Torben Orntoft, Meenhard Herlyn, Andrew J Caton, William Fredericks, Bruce Malkowicz, Christopher S Paterno, Alexandra S Carolin, David W Speicher, Emmanuel Skordalakes, Qihong Huang, Shoukat Dedhar, Katherine L B Borden, Frank J Rauscher 3rd
JournalCancer research (Cancer Res) Vol. 74 Issue 5 Pg. 1390-403 (Mar 1 2014) ISSN: 1538-7445 [Electronic] United States
PMID24590809 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Copyright©2014 AACR
Chemical References
  • LIM Domain Proteins
  • integrin-linked kinase
  • Protein-Serine-Threonine Kinases
  • Animals
  • Cell Movement (genetics)
  • Disease Progression
  • Fibroblasts (pathology)
  • HEK293 Cells
  • Humans
  • LIM Domain Proteins (genetics, metabolism)
  • MCF-7 Cells
  • Mice
  • Neoplasm Metastasis (genetics, pathology)
  • Neoplasms (genetics, metabolism, pathology)
  • Protein Binding (genetics)
  • Protein-Serine-Threonine Kinases (genetics, metabolism)
  • Signal Transduction (genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: