Decorin, a member of the small leucine-rich proteoglycan gene family, impedes tumor cell growth by down-regulating the epidermal growth factor receptor. Decorin has a complex binding repertoire, thus, we predicted that decorin would modulate the bioactivity of other tyrosine kinase receptors. We discovered that decorin binds directly and with high affinity (Kd = ∼1.5 nM) to Met, the receptor for hepatocyte growth factor (HGF). Binding of decorin to Met is efficiently displaced by HGF and less efficiently by internalin B, a bacterial Met ligand. Interaction of decorin with Met induces transient receptor activation, recruitment of the E3 ubiquitin ligase c-Cbl, and rapid intracellular degradation of Met (half-life = ∼6 min). Decorin suppresses intracellular levels of β-catenin, a known downstream Met effector, and inhibits Met-mediated cell migration and growth. Thus, by antagonistically targeting multiple tyrosine kinase receptors, decorin contributes to reduction in primary tumor growth and metastastic spreading.

Transport of cargoes by kinesin-1 is essential for many cellular processes. Nevertheless, the number of proteins known to recruit kinesin-1 via its cargo binding light chain (KLC) is still quite small. We also know relatively little about the molecular features that define kinesin-1 binding. We now show that a bipartite tryptophan-based kinesin-1 binding motif, originally identified in Calsyntenin is present in A36, a vaccinia integral membrane protein. This bipartite motif in A36 is required for kinesin-1-dependent transport of the virus to the cell periphery. Bioinformatic analysis reveals that related bipartite tryptophan-based motifs are present in over 450 human proteins. Using vaccinia as a surrogate cargo, we show that regions of proteins containing this motif can function to recruit KLC and promote virus transport in the absence of A36. These proteins interact with the kinesin light chain outside the context of infection and have distinct preferences for KLC1 and KLC2. Our observations demonstrate that KLC binding can be conferred by a common set of features that are found in a wide range of proteins associated with diverse cellular functions and human diseases.

Planar cell polarity (PCP) provides positional information to direct tissue patterning and morphogenesis. While much of the molecular detail of the pathway has been delineated in Drosophila, ensuing studies have shown considerable conservation of both the components and mechanisms of signaling in vertebrates. A recognized feature of PCP is the asymmetric localization of components that translates a global directional cue into a polarized downstream output. Here we discuss recent advances in the PCP field, from the organization of these asymmetric complexes to their upstream directional regulation by Wnt ligands. We also discuss the impact of Wnt/PCP signaling in disease and more specifically an emerging role in cancer progression.

During their egress, newly assembled vaccinia virus particles fuse with the plasma membrane and enhance their spread by inducing Arp2/3-dependent actin polymerization. Investigating the events surrounding vaccinia virus fusion, we discovered that vaccinia transiently recruits clathrin in a manner dependent on the clathrin adaptor AP-2. The recruitment of clathrin to vaccinia dramatically enhances the ability of the virus to induce actin-based motility. We demonstrate that clathrin promotes clustering of the virus actin tail nucleator A36 and host N-WASP, which activates actin nucleation through the Arp2/3 complex. Increased clustering enhances N-WASP stability, leading to more efficient actin tail initiation and sustained actin polymerization. Our observations uncover an unexpected role for clathrin during virus spread and have important implications for the regulation of actin polymerization.