Premium
LIMD2 is an intracellular activator of Integrin Linked Kinase(ILK) activity and GSK‐3/Akt/beta‐catenin signaling
Author(s) -
Dedhar Shoukat,
Awrey Shan
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.666.1
Subject(s) - integrin linked kinase , protein kinase b , cancer research , focal adhesion , microbiology and biotechnology , signal transduction , chemistry , integrin , pi3k/akt/mtor pathway , kinase , phosphorylation , biology , protein kinase a , cell , cyclin dependent kinase 2 , biochemistry
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 .