# Molecular Basis of ILK-Mediated Cell Adhesion

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $402,500

## Abstract

Virtually every cell in our body spends at least a portion of its life time on adhering to the extracellular matrix
(ECM). Such cell-to-ECM adhesion is primarily mediated by a class of heterodimeric (α/β) transmembrane
receptors, integrins. Upon activation, integrins bind ECM proteins (adhesion) and then transmit signals to
intracellular cytoskeleton via large multi-protein complexes called focal adhesions (FAs). This latter step is vital
to promote dynamic cell adhesive responses such as cell shape change, cell migration, and proliferation.
However, while much has been learned about integrin activation over the decades, the mechanism by which
integrin initiates signaling to the cytoskeleton via FAs is still poorly understood. To this end, we have been
focusing on integrin-linked kinase (ILK), a nascent mediator of FAs assembly and signaling. For >15 years, ILK
was thought to function as a key Ser/Thr kinase to phosphorylate integrin cytoplasmic tail and initiate the receptor
signaling. Highly upregulated in many cell adhesion-dependent diseases, ILK was also regarded as a “hot”
kinase target for drug development. However, structural studies from our laboratory uncovered that ILK contains
a severely degraded active site incapable of performing kinase catalysis. The finding, corroborated by extensive
biochemical and genetic data, led to a conceptual breakthrough as evidenced by dozens of reviews, hundreds
of re-themed research articles, and grants. However, a key issue still remains largely unresolved: without kinase
function, how does ILK mediate FAs assembly and signaling? This issue has broad relevance as there exist
many poorly understood pseudoenzymes including pseudokinases that occupy ~10% of human kinome. In a
most recent study, we discovered that by forming a tight complex with FA adaptors PINCH and Parvin (IPP), ILK
triggers specific actin filament bundling – a process known to generate force/mechanical signal to promote
cytoskeleton reorganization and dynamic cell adhesion. We further found that such actin bundling is orchestrated
by two previously unrecognized actin binding motifs within the ILK-centered IPP, one from PINCH and the other
from Parvin. Strikingly, this process is also sensitized by Mg-ATP bound to the pseudoactive site of ILK and
impaired by a novel inhibitor we have developed. Our findings thus signify a new milestone towards resolving
the mystery of ILK as a pseudokinase in mediating cell adhesion and signaling. We propose to continue our
investigation by focusing on three following aims: (i) to resolve a puzzle of how ILK is localized to nascent FAs
– the first step for the ILK action; (ii) to elucidate how ILK acts as a unique protein docking center to mediate
different signaling pathways; (iii) to determine detailed molecular basis of non-catalytic roles of ILK-bound
MgATP in fine-tuning the ILK-mediated signaling. These aims reflect a strong momentum of our program, which
has reached a critical phase towards establ...

## Key facts

- **NIH application ID:** 10375403
- **Project number:** 5R01HL058758-22
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** JUN QIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 1999-01-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375403

## Citation

> US National Institutes of Health, RePORTER application 10375403, Molecular Basis of ILK-Mediated Cell Adhesion (5R01HL058758-22). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10375403. Licensed CC0.

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