LIMD2 is an intracellular activator of Integrin Linked Kinase(ILK) activity and GSK‐3/Akt/beta‐catenin signaling
Bibliographic record
Abstract
Integrin‐Linked Kinase (ILK) is an intracellular, focal adhesion, scaffold protein that couples beta 1‐integrins and growth factors to actin cytoskeletal organization and signal transduction via GSK‐3 beta and Akt. ILK has an atypical kinase catalytic domain, and has been considered to be a pseudokinase. Here, we demonstrate that a small LIM domain only protein, LIMD2, which is highly overexpressed in several types of cancers, and which interacts directly with ILK within the kinase domain ( Peng, H et al, Cancer Res, 2014), forms a complex with ILK in cancer cells and stimulates ILK kinase activity. LIMD2 overexpression results in the stimulation of the phosphorylation of GSK‐3 beta on Ser‐9, as well as of Akt on Ser‐473, in an ILK‐dependent manner. Furthermore we demonstrate a striking LIMD2 induced stimulation of phosphorylation of beta‐catenin on Ser‐552, shown previously to be a target of Akt, leading to 14.3.3‐dependent stablization of beta‐catenin and stimulation of Lef/TCF transcriptional activity that results in tumor cell invasion (Fang et al. J Biol Chem, 2007). Since LIMD2 upregulation in tumor cells is associated with increased cell invasion and metastasis, we examined the effect of inhibiting LIMD2 induced ILK activity on breast, thyroid and pancreatic cell invasion through collagen and matrigel. As expected, overexpression of LIMD2 induced tumor cell invasion, and this invasion was blocked by ILK siRNA or by a specific pharmacological inhibitor of ILK, QLT‐0267. Inhibition of ILK in these cells also resulted in dramatic suppression of Akt Ser‐473 and beta‐catenin Ser‐552 phosphorylation as well as of LEF‐TCF transcrptional activity. In summary, we describe a new paradigm for the intracellular activation of low activity protein kinases through protein‐protein interactions. Specifically we identify a new signaling axis through the activation of ILK by LIMD2, which results in the stimulation of a GSK‐3/Akt/Beta‐catenin pathway important in tumor cell invasion. Support or Funding Information Supported by funds from the Cancer Research Society, Quebec, Canada This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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".