Protein-protein interactions: a mechanism regulating the anti-metastatic properties of Nm23-H1

Abstract

Nm23-H1, also known as NDPK-A, was the first of a class of metastasis suppressor genes to be identified. Overexpression of Nm23-H1 in metastatic cell lines (melanoma, breast carcinoma, prostate, colon, hepatocellular, and oral squamous cell carcinoma) reduced cell motility in in vitro assays and metastatic potential in xenograft models, without a significant effect on primary tumor size. The mechanism of Nm23-H1 suppression of metastasis, however, is incompletely understood. Nm23-H1 has been reported to bind proteins, including those in small G-protein complexes, transcriptional complexes, the Map kinase, the TGF-β signaling pathways and the cytoskeleton. Evidence supporting these associations is presented together with evidence of resultant biochemical and phenotypic consequences of association. Cumulatively, the data suggest that part of the anti-metastatic function of Nm23-H1 lies in pathways that it interrupts via binding and inactivation of proteins.

Fig. 1

A proposed model showing the interactions of Nm23-H1 with cellular pathways. The depicted tumor cell is polarized and moving upwards in response to a chemoattractant, while still maintaining a cell–cell interaction to a stromal cell below it. a The leading edge of the cell showing a representation of the focal adhesion structure, including pathways involved in cell motility that could be modulated by Nm23-H1 as shown in b. The leading edge is driven by actin polymerization-mediated protrusions that point in the direction of cell movement. The JNK, Rho, and Map kinase pathways are involved in cell signaling inducing motility towards an external stimulus. b Depiction of the trailing edge of the cell showing a link between Nm23-H1 anti-motility properties and the regulatory effect on its described binding partners. Motility-associated pathways can be inhibited by the interaction of their constituents to Nm23-H1. The binding of Nm23-H1 to Dbl1 can modulate the Rho pathway, while Tiam1 binding can inhibit JNK and association with Ksr1 can regulate the Map kinase pathway. Nm23-H2 can interact with Icap-1α inhibiting its association with the FAK complex. c Cell–cell interaction between the polarized cell and another nearby stromal cell. Nm23-H1 can bind to Vimentin, leading to a localized thickening of the intermediate filaments. In addition, it can bind to the Plakoglobin complex in the area of cell–cell contact