Nm23-H1 regulates contact inhibition of locomotion which is affected by ephrin-B1

Abstract

SummaryContact inhibition of locomotion (CIL) is the process by which cells stop the continual migration in the same direction after collision with another cell. Highly invasive malignant cells exhibit diminished CIL when they contact stromal cells, which allows invasion of the tissue by tumors. We show that Nm23-H1 is essential for the suppression of Rac1 through inactivation of Tiam1 at the sites of cell-cell contact, which plays a pivotal role in CIL. U87MG cells show CIL when they contact normal glia. In spheroid confrontation assays U87MG cells showed only limited invasion of the glial population, but reduction of Nm23-H1 expression in U87MG cells abrogated CIL resulting in invasion. In U87MG cells, Nm23-H1 is translocated to the sites of contact with glia through association with a-catenin and N-cadherin. Mutants of Nm23-H1, which lacked the binding ability with Tiam1, or a-catenin did not restore CIL. Moreover, the expression of ephrin-B1 in tumor cells disrupted CIL and promoted invasion. As one mechanism, ephrin-B1 inhibits the association of Nm23-H1 with Tiam1, which contributes for activation of Rac1. These results indicate a novel function of Nm23-H1 to control CIL, and its negative regulation by ephrin-B1.

Contact inhibition of locomotion probabilities drive solitary versus collective cell migration

“…In many cases, homophilic binding between cadherin receptors on adjacent cells underlies the polarity signal, although the specific cadherin isoform and downstream signalling pathways involved are perhaps context-specific. Moreover, binding of ephrin ligands to cognate Eph receptors has been shown to underlie CIL in several cell types, including neural crest cells and prostate cancer cells [6,15,40]. Despite these inroads in understanding that highlight which molecules might be involved in the process, no study to date has quantitatively described the probabilistic nature of CIL, its relative strength, and its dependence on context.…”

The actions of NME1/NDPK-A and NME2/NDPK-B as protein kinases

“…33 The metastasis suppressor activity of Nme1 has been demonstrated in many cancers except leukemias, lymphomas, and neuroblastoma. 34,35 Multiple aspects of metastasis have been implicated in Nme1 suppression, including cell adhesion, [36][37][38] motility and signaling, [39][40][41][42][43][44][45] and proteolysis. 46 As discussed by Kaetzel et al, 38 Nme1 promotes genomic stability in melanoma through direct interactions with at least two DNA repair pathways, nucleotide excision repair and doublestrand break repair.…”

Progress on Nme (NDP kinase/Nm23/Awd) gene family-related functions derived from animal model systems: studies on development, cardiovascular disease, and cancer metastasis exemplified

“…Surprisingly, no single set of pathways has been shown to be Nme1-dependent. Rather, a bewildering host of adhesion molecules (Boissan et al 2010;Fournier et al 2002;Kaetzel et al 2014), motility factors, signaling pathways (Hartsough et al 2002;Masoudi et al 2013;Murakami et al 2008;Otero 1997;Otsuki et al 2001;Roymans et al 2000;Seong et al 2007;Tanaka et al 2012;You et al 2014), proteolytic events (Khan et al 2001), EMT hallmarks (Zhao et al 2013), and other transcriptional programs (Horak et al 2007) have been functionally linked to Nme1. A new, important finding showed that lysosomal cysteine cathepsins degraded Nme1 proteins under the direction of C-Abl and Arg, limiting invasiveness (Fiore et al 2014).…”