A new central scaffold for metastasis: parsing HEF1/Cas-L/NEDD9

Abstract

Greater understanding of metastasis is required to improve cancer treatment outcomes. Recently, changes in expression of the scaffold protein HEF1/CAS-L/NEDD9 were found to be a potent prometastatic stimulus in melanoma and other cancers. Mechanistic studies suggest diverse cellular roles of HEF1 and highlight its importance in the response to extracellular cues that drive invasion and metastasis. As a metastatic "hub" for signaling in cancer, HEF1 may provide a useful target for drug discovery efforts.

A. Schematic of structure of the HEF1/NEDD9/CasL protein. Human HEF1 is 834 amino acids; key functional domains include an amino-terminal SH3 domains, which binds FAK; a “substrate domain” (SD) containing multiple embedded SH2 binding sites, analogous to the mechanosensing domain of p130Cas recently described by Sawada et al.; a likely four-helix bundle, based on molecular modeling of primary sequence of HEF1 against the crystal coordinates for the conserved region of p130Cas (results not shown); and an evolutionarily conserved C-terminal domain, which binds Src family kinases and other proteins (indicated with a “?” as details of structure remain unknown). B. HEF1 (indicated in bright yellow, with “H”) is a component of the integrin dependent Src-FAK-Crk migration signaling cascade; influences cellular homing through CHAT/CXCR4; engages in crosstalk with the Ras pathway; is an intermediate in TGF-β-dependent signaling; activates the centrosomal Aurora-A/Ajuba/TPX2 machinery governing mitotic entry and cytokinesis; and activates Aurora-A/HDAC6 at the basal body to initiate ciliary disassembly. C. Curated online resources (based on experimentally well-validated protein interaction data) indicate numerous direct HEF1 interactions with cancer-related signaling pathways. Blue lines indicate protein interactions; many HEF1 partners also take part in extensive self-interactions within functional clusters that are likely augmented by increased HEF1 levels. Clusters shown in rose are particularly relevant to FAK/Src/integrin; in green, to CHAT/Rap1; in blue, to Aurora A; in gold, to TGF-β/SMADs; in yellow, all others. All HEF1-only interactions present in online databases are shown as blue lines; for contrast, common interactions of BCAR1/p130Cas are also shown as dashed pink lines. Interactions between all other proteins (including functional as well as physical interactions) are shown in green. For clarity, only interactions relevant to the discussion in this review are shown. Data on protein-protein interactions were collected in Cytoscape (http://cytoscape.org/), combining data from a Bionet plugin (http://err.bio.nyu.edu/cytoscape/bionetbuilder/), and EMBL String (string.embl.de/), with each retrieving information from several databases, including DIP (http://dip.doe-mbi.ucla.edu/), BIND (http://www.bind.ca/), KEGG (http://www.genome.jp/kegg/), Prolinks (http://mysql5.mbi.ucla.edu/cgi-bin/functionator/pronav), HPRD (http://www.hprd.org/), and The BioGrid (http://www.thebiogrid.org/).