Differential regulation of myosin X movements by its cargos, DCC and neogenin

Abstract

SummaryMyosin X (Myo X), also known as MYO10, is an unconventional actin-based motor protein that plays an important role in filopodium formation. Its intra-filopodia movement, an event tightly associated with the function of Myo X, has been extensively studied. However, how the motor activity of Myo X and the direction of its movements are regulated remains largely unknown. In our previous study, we demonstrated that DCC (for 'deleted in colorectal carcinoma') and neogenin (neogenin 1, NEO1 or NGN), a family of immunoglobindomain-containing transmembrane receptors for netrins, interact with Myo X and that DCC is a cargo of Myo X to be delivered to the neurites of cultured neurons. Here, we provide evidence for DCC and neogenin as regulators of Myo X. DCC promotes movement of Myo X along basal actin filaments and enhances Myo-X-mediated basal filopodium elongation. By contrast, neogenin appears to suppress Myo X movement on the basal side, but increases its movement towards the apical and dorsal side of a cell, promoting dorsal filopodium formation and growth. Further studies have demonstrated that DCC, but not neogenin, enhances integrin-mediated tyrosine phosphorylation of focal adhesion kinase and basal F-actin reorganization, providing a cellular mechanism underlying their distinct effects on Myo X. These results thus demonstrate differential regulatory roles on Myo X activity by its cargo proteins, DCC and neogenin, revealing different cellular functions of DCC and neogenin.

Headless Myo10 Is a Negative Regulator of Full-length Myo10 and Inhibits Axon Outgrowth in Cortical Neurons

“…Myo10 can bind to the netrin receptors DCC and neogenin (6,23,28,29) and is required to localize DCC to neurites (28). However, in this study, outgrowth was not stimulated by any exogenous guidance cue or growth factor, indicating that Myo10 is required for baseline axon outgrowth independent of external cues.…”

“…Myo10 localizes to the tips of filopodia (2-6), moves within filopodia (6 -10), and induces the formation of filopodia (4,6,7,10,11). Given the importance of filopodia in neuronal development, particularly in axon outgrowth and branching (12)(13)(14)(15), Myo10 is likely to have critical functions in neuronal development.…”

“…Myo10 is required for the distribution of DCC to the periphery (28), whereas DCC and neogenin have different effects on the type of filopodia induced by Myo10 (6). In the chicken spinal cord, shRNA to Myo10 impaired crossing of commissural axons across the midline (28), although it is not clear whether this defect resulted from incorrect guidance or insufficient outgrowth.…”

MyTH4-FERM myosins in the assembly and maintenance of actin-based protrusions

“…Myo10 also binds to transmembrane netrin receptors DCC and neogenin, and disruption of these interactions results in defects of axonal projection and path finding [5,7,44]. These cargoes have been shown to differentially regulate Myo10 activity and induction of filopodia formation, with DCC enhancing basal filopodia elongation and neogenin promoting dorsal filopodia growth [45]. VE-cadherin and N-cadherin are Myo10 cargoes that function in the formation of early endothelial cell-cell contacts and neuronal radial migration, respectively [46,47].…”

Immunomodulatory Effect of Mesenchymal Stem Cells on B Cells

“…Multiple studies have demonstrated that MSCs inhibit effector T cell proliferation and cytokine release through mechanisms that are cell-contact-dependent (PD-L1, Augello et al, 2005; B7-H4, Xue et al, 2010; ICAM1; VCAM1, Ren et al, 2010) and contact-independent (IDO, Ge et al, 2010; PGE 2 , Najar et al, 2010; Duffy et al, 2011b; HLA-G, Selmani et al, 2009; TGFβ, Liu et al, 2012; galectins, Sioud, 2011). In vivo models have shown that MSCs have an indirect effect on T cell activation by inhibition of maturation of DCs.…”