Integrin-linked kinase (ILK): A "Hot" therapeutic target

Tn. Yoganathan et al., Integrin-linked kinase (ILK): A "Hot" therapeutic target, BIOCH PHARM, 60(8), 2000, pp. 1115-1119
Citations number
Categorie Soggetti
Pharmacology & Toxicology
Journal title
ISSN journal
0006-2952 → ACNP
Year of publication
1115 - 1119
SICI code
Integrin-mediated cell adhesion is known to regulate gene expression throug h the activation of transcription factors. We have recently revealed that t hese activations are mediated through integrin-linked kinase (ILK). ILK is an ankyrin repeat-containing serine-threonine protein kinase that can inter act directly with the cytoplasmic domain of the beta 1 and beta 3 integrin subunits and whose kinase activity is modulated by cell-extracellular matri x interactions. We have shown that ILK overexpression results in the transl ocation of beta-catenin to the nucleus, which then forms a complex formatio n with the lymphoid enhancer binding factor 1 (LEF-1) transcription factor, subsequently activating the transcriptional activity of promoters containi ng LEF-1 response elements. ILK phosphorylates the glycogen synthase kinase -3 (GSK-3), which inhibits GSK-3 activity. We have demonstrated that ILK st imulates activator protein-1 transcriptional activity through GSK-3 and the subsequent regulation of the c-Jun-DNA interaction. ILK also phosphorylate s protein kinase B (PKB/Akt) and stimulates its activity. We have shown tha t ILK is an upstream effector of the phosphatidylinositol 3-kinase-dependen t regulation of PKB/Akt. ILK has been shown to phosphorylate PKB/Akt on Ser -473 in vitro and in vivo. Our results clearly indicate that ILK is a key e lement in the regulation of integrin signaling as well as growth factor and Wnt signaling pathways. PTEN (phosphatase and tensin homolog detected on c hromosome 10) is a tumor suppressor gene located on chromosome 10q23 that e ncodes a protein and phospholipid phosphatase. It is now estimated that ina ctivation mutants of PTEN exist in 60% of all forms of solid rumors. Loss o f expression or mutational inactivation of PTEN leads to the constitutive a ctivation of PKB/Akt via enhanced phosphorylation of Thr-308 and Ser-473. W e have demonstrated that the activity of ILK is constitutively elevated in PTEN mutant cells. A small molecule ILK inhibitor suppresses the phosphoryl ation of PKB at the Ser-473 but not the Thr-308 site in the PTEN mutant cel ls. These results indicate that inhibition of ILK may be of significant val ue in solid tumor therapy. BIOCHEM PHARMACOL 60;8:1115-1119, 2000. (C) 2000 Elsevier Science Inc.