Abstract 992: LIMD2 is a small LIM-only protein overexpressed in metastatic lesions which regulates cell motility and tumor progression by directly binding to and activating the integrin-linked-kinase
Bibliographic record
Abstract
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 and hence are a prime target for deregulation during tumor progression and metastasis. The LIM domain is a modular Zn finger structure, often found tandemly repeated in proteins. These LIM arrays often serve as scaffolds for assembling signal transduction apparatus. In this work, we characterize LIMD2 which is unique in that it encodes a single LIM domain. LIMD2 was originally identified as a transcript overexpressed in metastatic lesions but absent in the matched primary tumor from the same patient suggesting that it may be either a marker or effector of metastatic spread. We have shown that LIMD2 levels in fresh and archival tumors positively correlate with cell motility, metastatic potential and tumor grade in many different tumor types 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. Tumor cells with poor metastatic capability are converted to highly motile, invasive cells by expression of LIMD2 suggesting a dominant gain of function action. To understand the molecular mechanisms of its biological effects we determined its solution structure using NMR. The structure studies of LIMD2 revealed a classic LIM-domain structure containing a rigid hydrophobic core which bound 2 molecules of Zn. The 3D structure of LIMD2 was most highly related to the LIM1 domain of PINCH1, a core component of the Integrin Linked Kinase-Parvin-Pinch (IPP) complex. The IPP complex plays a key role in cell-cell and cell matrix interaction by transducing signals from membrane bound integrins to the nucleus. Structural and biochemical analyses revealed that LIMD2 bound directly to the kinase domain of ILK near the active site and strongly activated ILK kinase activity in vitro. Immunolocalization studies showed that LIMD2 and components of the IPP complex co-existed in focal adhesion plaques. Cells which were null for ILK failed to respond to the induction of motility and invasion by ectopic expression of LIMD2. This strongly suggests that LIMD2 potentiates its biological effects through direct interactions with ILK, a signal transduction pathway firmly linked to cell motility and invasion. In summary, we have defined LIMD2 as 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. Citation Format: Hongzhuang Peng, Mehdi Taleb Zadeh 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 S. Dedhar, Katherine L. B. Borden, Frank J. Rauscher. LIMD2 is a small LIM-only protein overexpressed in metastatic lesions which regulates cell motility and tumor progression by directly binding to and activating the integrin-linked-kinase. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 992. doi:10.1158/1538-7445.AM2014-992
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".