Proteins that communicate signals from the cytoskeleton to the nucleus are prime targets for effectors of
metastasis as they often transduce signals regulating adhesion, motility, and invasiveness.
LIM domain proteins shuttle between the cytoplasm and the nucleus, and bind to partners in both compartments, often coupling changes in gene expression to extracellular cues. In this work, we characterize LIMD2, a mechanistically undefined LIM-only
protein originally found to be overexpressed in metastatic lesions but absent in the matched primary
tumor. LIMD2 levels in fresh and archival
tumors positively correlate with cell motility, metastatic potential, and grade, including bladder,
melanoma, breast, and thyroid
tumors. LIMD2 directly contributes to these cellular phenotypes as shown by overexpression, knockdown, and reconstitution experiments in cell culture models. The
solution structure of LIMD2 that was determined using nuclear magnetic resonance revealed a classic LIM-domain structure that was highly related to LIM1 of PINCH1, a core component of the
integrin-linked kinase-parvin-pinch complex. Structural and biochemical analyses revealed that LIMD2 bound directly to the
kinase domain of
integrin-linked kinase (ILK) near the active site and strongly activated ILK
kinase activity. Cells that were null for ILK failed to respond to the induction of invasion by LIMD2. This strongly suggests that LIMD2 potentiates its
biologic effects through direct interactions with ILK, a signal transduction pathway firmly linked to cell motility and invasion. In summary, LIMD2 is a new component of the signal transduction cascade that links
integrin-mediated signaling to cell motility/metastatic behavior and may be a promising target for controlling
tumor spread.