Integrin-linked kinase – essential roles in physiology and cancer biology

Abstract

Integrin-linked kinase (ILK) is a multifunctional intracellular effector of cell-matrix interactions and regulates many cellular processes, including growth, proliferation, survival, differentiation, migration, invasion and angiogenesis. The use of recently developed Cre-lox-driven recombination and RNAinterference technologies has enabled the evaluation of the physiological roles of ILK in several major organ systems. Significant developmental and tissue-homeostasis defects occur when the gene that encodes ILK is deleted, whereas the expression of ILK is often elevated in human malignancies. Although the cause(s) of ILK overexpression remain to be fully elucidated, accumulating evidence suggests that its oncogenic capacity derives from its regulation of several downstream targets that provide cells with signals that promote proliferation, survival and migration, supporting the concept that ILK is a relevant therapeutic target in human cancer. Furthermore, a global analysis of the ILK 'interactome' has yielded several novel interactions, and has revealed exciting and unexpected cellular functions of ILK that might have important implications for the development of effective therapeutic agents.

Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer

“…Previous studies have shown elevated expression of ILK in number of human cancers (McDonald et al, 2008a). Consistent with this view, immunohistochemical analysis of mammary tumors derived from transgenic mice expressing activated ErbB2 under the transcriptional control of the MMTV promoter with ILK-specific antibodies revealed that they expressed elevated levels of ILK protein (Figure 3a, NIC ILK wt/wt panel).…”

“…The integrin-linked kinase (ILK) is a modular protein with separate scaffolding and kinase-like domains that mediates the physical and functional coupling of integrins to growth factor signaling (Hannigan et al, 2005;McDonald et al, 2008a). ILK modulates integrinmediated adhesion by directly interacting with the cytoplasmic tails of b1-or b3-integrin receptors (Hannigan et al, 1996), and complexes with Parvin A/B (Attwell et al, 2003;Mongroo et al, 2004) and PINCH (Tu et al, 1999).…”

Integrins as therapeutic targets: lessons and opportunities

“…Integrin-linked kinase (ILK) is also a potential target in cancer [172][173] , although there is the possibility of non-specific actions on other kinases. A number of small-molecule inhibitors of ILK have been tested in in vitro models of cancer and metastasis [174][175] .…”

Integrin signalling adaptors: not only figurants in the cancer story

“…The expression of ILK has been analysed in a large number of human malignancies [29][30][31] and is often found to be elevated and associated with tumour progression and shortened survival (Table 1). Increased ILK expression has been associated with more differentiated areas of malignant gastrointestinal, renal, neural and bone marrow tumours, suggesting that ILK might be also an indicator of differentiation 29,32 .…”

“…The use of RNAi and antisense oligonucleotides to downregulate ILK expression and small molecule inhibitors to abrogate its kinase activity, has been shown to reverse ILK oncogenic effects in a variety of cancers. Indeed inhibition of either ILK expression or its activity results in decreased cell migration and invasion, metastasis formation, induction of apoptosis in vitro 30,129,130 and in vivo [131][132][133] . In addition, on the basis of the new role of ILK in mitosis 103,104 , the potential targeting of ILK as an anti-mitotic chemotherapeutic might provide a promising alternative to the chemotherapeutics avoiding severe toxic side effects and drug resistance.…”