Amplification of F-Actin Disassembly and Cellular Repulsion by Growth Factor Signaling

Abstract

SUMMARY Extracellular cues that regulate cellular shape, motility, and navigation are generally classified as growth-promoting (i.e., growth factors/chemoattractants and attractive guidance cues) or growth-preventing (i.e., repellents and inhibitors). Yet, these designations are often based on complex assays and undefined signaling pathways, and thus may misrepresent direct roles of specific cues. Herein, we find that a recognized growth-promoting signaling pathway amplifies the F-actin disassembly and repulsive effects of a growth-preventing pathway. Focusing on Semaphorin/Plexin repulsion, we identified an interaction between the F-actin-disassembly enzyme Mical and the Abl tyrosine kinase. Biochemical assays revealed Abl phosphorylates Mical to directly amplify Mical Redox-mediated F-actin disassembly. Genetic assays revealed Abl allows growth factors and Semaphorin/Plexin repellents to combinatorially increase Mical-mediated F-actin disassembly, cellular remodeling, and repulsive axon guidance. Similar roles for Mical in growth factor/Abl-related cancer cell behaviors further revealed contexts in which characterized positive effectors of growth/guidance stimulate such negative cellular effects as F-actin disassembly/repulsion.

ABL to Integrate Opposing Cellular Growth Signals

“…Growth factor signaling has long been known to stimulate cellular growth and motility. That it might also directly promote repulsive signaling, however, is a surprising finding reported by Yoon et al (2017) in this issue of Developmental Cell.…”

“…One might assume that when Sema-phorin/Plexin and growth factor signaling occur simultaneously, the opposing signals might weaken or even cancel each other out, slowing down growth or motility. Surprisingly, a study from the Terman lab (Yoon et al, 2017) reports an interesting signaling mechanism in which positive growth factor signaling enhances repulsive Semaphorin responses in neurons and tumor cells. In other words, when cells receive-simultaneously-both repulsive and growth-promoting signals, the repulsive signaling and response becomes even stronger.…”

“…In other words, when cells receive-simultaneously-both repulsive and growth-promoting signals, the repulsive signaling and response becomes even stronger. Yoon et al (2017) focused on the regulation of Mical, a key effector of Semaphorin/Plexin signaling. Mical is a redoxcontrolled monooxygenase, oxidizing and thereby depolymerizing F-actin (Hung et al, 2010).…”

“…Figure adapted from Cinalli and Lehmann, 2013. growth cone mobility and is therefore considered a mediator of repulsive signaling. Yoon et al (2017) now find that the non-receptor tyrosine kinase Ableson (Abl), which is often activated during growth factor signaling (Greuber et al, 2013;Khatri et al, 2016), can directly bind, via its SH3 domain, to a PXXP motif of Mical. Abl then phosphorylates a tyrosine residue located in Mical's redox-sensing domain.…”

“…The static phenotypic endpoint-effects of such genetic interactions are, however, notoriously difficult to interpret, given that the underlying dynamic changes in actin polymerization cannot be resolved directly (Wernet and Desplan, 2015). A strength of the study by Yoon et al (2017) is that it meets this challenge by identifying a system in which it is possible to directly monitor Plexin-mediated actin polymerization in vivo at the single-cell resolution (Hung et al, 2010). Specifically, the formation of bristles on the Drosophila epithelial surface (i.e., cuticle) is a manifestation of highly organized intracellular actin assembly.…”