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ILK Signaling

Integrin linked kinase (ILK) is an intracellular protein whose main function is to connect integrins to the cytoskeleton. Different domains of ILK interact with different proteins. For example, the C-terminal region interacts with several actin binding adapter proteins, while ANK repeats bind to PINCH protein and ILKAP. ILKAP negatively regulates ILK activity. PH domain of ILK binds to PIP3...

ILK Signaling

Pathway Summary

Integrin linked kinase (ILK) is an intracellular protein whose main function is to connect integrins to the cytoskeleton. Different domains of ILK interact with different proteins. For example, the C-terminal region interacts with several actin binding adapter proteins, while ANK repeats bind to PINCH protein and ILKAP. ILKAP negatively regulates ILK activity. PH domain of ILK binds to PIP3. The tumor suppressor PTEN dephosphorylates PIP3 to PIP2, resulting in the inhibition of ILK activity. The kinase domain of ILK binds to the cytoplasmic tails of β-integrins, PDK1, parvins, kindlin-2/MIG2 and Paxillin. Paxillin interacts with α-parvin and β-parvin, which then bind to F-actin directly or indirectly through binding to Paxillin or Hic5 or α-actinin. α-parvin also binds to TESK1, whereas β-parvin binds to PIX-α. This influences actin remodeling through GTPases, Rac1 and CDC42, by activating the cytoskeletal adhesion complexes. TESK1 mainly phosphorylates Cfl and induces actin cytoskeletal reorganization, whereas Hic5 regulates apoptosis. α-parvin and β-parvin compete for binding to ILK and have opposite effects on ILK kinase activity.ILK binds PINCH and α-parvin or β-parvin to form PINCH-ILK-parvin ternary complexes. Formation of these complexes is required for preventing degradation of ILK, PINCH and parvins. Their recruitment is mediated by interaction with proteins such as β1-integrin, MIG2/Kind2 and Paxillin. ILK connects via PINCH to NCK2, which binds to DOCK180 and mediates actin cytoskeleton dynamics. PINCH isoforms bind to RTKs through NCK2, thereby coupling growth factor signaling to integrin signaling. PINCH and NCK2 interaction elevates the level of intracellular PIP3 through PI3K activation, thereby enhancing ILK signaling. PINCH also binds to RSU1 and Tβ4 to influence JNK signaling and cell migration. Cytokines such as TNF-α activate the integrin-ILK-GSK3-p130CAS-JNK signaling pathway and regulate Occludin levels near junction points. TNF-α-induced activation of Rac1 activates JNK in order to regulate AP-1 mediated MMP2/9 gene expression and tissue morphogenesis.On integrin engagement with ECM, PI3K is activated through FAK and co-activation by growth factors. PI3K activates ILK which binds α-parvin and Paxillin and gets recruited to focal adhesion plaques. At the focal adhesion plaques, ILK activity is crucial for maintaining upstream signaling to β1-integrins and downstream signaling to AKT, GSK3 and PHI1. These events promote survival by inhibiting BAD, caspase 3/9 and cell cycle transition by blocking proteolysis of Cyclin D1. Other downstream targets of ILK-induced AKT include mTOR, NF-κB and α-NAC. mTOR activates HIF1α that along with NF-κB controls the gene expression of iNOS, COX2 and VEGF. ILK phosphorylation of GSK3β also inhibits β-catenin and LEF/TCF interaction, which in turn regulates the function of Myc, cadherins and CREB. ILK may directly activate CREB through the ERK-MSK-1/2 signaling route.In addition, ILK signaling also activates SNAI1/2. SNAI act as repressors of E-cadherin expression. SNAI down-regulate Desmoplakin, epithelial Mucin-1 and Keratin-18/Cytokeratin-18 and up-regulate Vimentin and Fibronectin. ILK also has important roles in cancer progression, and has emerged as a valid therapeutic target in cancer.

ILK Signaling Genes list

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