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The recruitment of signaling proteins into activated receptor tyrosine kinases (RTKs) to produce rapid, high-fidelity downstream response is exposed to the ambiguity of random diffusion to the target site. Liquid-liquid phase separation (LLPS) overcomes this by providing elevated, localized concentrations of the required proteins while impeding competitor ligands. Here, we show a subset of phosphorylation-dependent RTK-mediated LLPS states. We then investigate the formation of phase-separated droplets comprising a ternary complex including the RTK, (FGFR2); the phosphatase, SHP2; and the phospholipase, PLCγ1, which assembles in response to receptor phosphorylation. SHP2 and activated PLCγ1 interact through their tandem SH2 domains via a previously undescribed interface. The complex of FGFR2 and SHP2 combines kinase and phosphatase activities to control the phosphorylation state of the assembly while providing a scaffold for active PLCγ1 to facilitate access to its plasma membrane substrate. Thus, LLPS modulates RTK signaling, with potential consequences for therapeutic intervention. [Display omitted] • Phosphorylated RTKs undergo phase separation with downstream effectors • Phosphorylation-dependent multivalent interaction drives FGFR2-SHP2 phase separation • The FGFR2-SHP2 complex colocalizes PLCγ1 to its plasma membrane substrate • Enzymatic activities are regulated within the FGFR2-SHP2-PLCγ1 membraneless droplets Lin et al. demonstrate that phosphorylated RTKs undergo liquid-liquid phase separation upon the recruitment of downstream proteins. Focusing on the RTK FGFR2, this process is shown to modulate enzymatic activities within the subcellular membraneless compartment. [ABSTRACT FROM AUTHOR]

Summary: Receptor tyrosine kinase activity is known to occur in the absence of extracellular stimuli. Importantly, this “background” level of receptor phosphorylation is insufficient to effect a downstream response, suggesting that strict controls are present and prohibit full activation. Here a mechanism is described in which control of FGFR2 activation is provided by the adaptor protein Grb2. Dimeric Grb2 binds to the C termini of two FGFR2 molecules. This heterotetramer is capable of a low-level receptor transphosphorylation, but C-terminal phosphorylation and recruitment of signaling proteins are sterically hindered. Upon stimulation, FGFR2 phosphorylates tyrosine residues on Grb2, promoting dissociation from the receptor and allowing full activation of downstream signaling. These observations establish a role for Grb2 as an active regulator of RTK signaling. [ABSTRACT FROM AUTHOR]

RNA flow between organisms has been documented within and among different kingdoms of life. Recently, we demonstrated horizontal RNA transfer between honeybees involving secretion and ingestion of worker and royal jellies. However, how the jelly facilitates transfer of RNA is still unknown. Here, we show that worker and royal jellies harbor robust RNA-binding activity. We report that a highly abundant jelly component, major royal jelly protein 3 (MRJP-3), acts as an extracellular non-sequence-specific RNA-aggregating factor. Multivalent RNA binding stimulates higher-order assembly of MRJP-3 into extracellular ribonucleoprotein granules that protect RNA from degradation and enhance RNA bioavailability. These findings reveal that honeybees have evolved a secreted dietary RNA-binding factor to concentrate, stabilize, and share RNA among individuals. Our work identifies high-order ribonucleoprotein assemblies with functions outside cells and organisms. • Worker and royal jellies harbor robust RNA-binding activity • Major royal jelly protein 3 (MRJP-3) is the dietary RNA-binding factor • RNA stimulates higher-order assembly of MRJP-3 into extracellular RNP granules • MRJP-3 granules concentrate, stabilize, and enhance environmental RNA bioavailability Honeybees share RNA between individuals through secretion and ingestion of worker and royal jellies. Maori et al. identify a jelly factor, MRJP-3, that forms extracellular ribonucleoprotein granules that concentrate, protect, and enhance RNA uptake. They propose that MRJP-3 facilitates RNA transfer that drives social immunity and signaling among bees. [ABSTRACT FROM AUTHOR]