Eph/Ephrin-Based Protein Complexes: The Importance of cis Interactions in Guiding Cellular Processes

Abstract

Although intracellular signal transduction is generally represented as a linear process that transmits stimuli from the exterior of a cell to the interior via a transmembrane receptor, interactions with additional membrane-associated proteins are often critical to its success. These molecules play a pivotal role in mediating signaling via the formation of complexes in cis (within the same membrane) with primary effectors, particularly in the context of tumorigenesis. Such secondary effectors may act to promote successful signaling by mediating receptor-ligand binding, recruitment of molecular partners for the formation of multiprotein complexes, or differential signaling outcomes. One signaling family whose contact-mediated activity is frequently modulated by lateral interactions at the cell surface is Eph/ephrin (EphA and EphB receptor tyrosine kinases and their ligands ephrin-As and ephrin-Bs). Through heterotypic interactions in cis, these molecules can promote a diverse range of cellular activities, including some that are mutually exclusive (cell proliferation and cell differentiation, or adhesion and migration). Due to their broad expression in most tissues and their promiscuous binding within and across classes, the cellular response to Eph:ephrin interaction is highly variable between cell types and is dependent on the cellular context in which binding occurs. In this review, we will discuss interactions between molecules in cis at the cell membrane, with emphasis on their role in modulating Eph/ephrin signaling.

Cisinhibition of co-expressed DIPs and Dprs shapes neural development

“…Here, we combine in vitro cell assays and in vivo genetic manipulations to demonstrate that DIPs and Dprs can interact in cis to inhibit trans interactions. Cis inhibition appears to be a widespread phenomenon as it has been demonstrated in several other systems including Notch/Delta 30,31 , ephrins/Ephs 32 , semaphorins/plexins 33 , neurexins/neuroligins 34 , sidekicks 23 , and IgLONs 35–37 . Cis inhibition has also been shown to be important for several developmental processes such as neurogenesis, axon guidance and neural tissue patterning 38,39 .…”

Controlled Plasma Membrane Delivery of FGFR1 and Modulation of Signaling by a Novel Regulated Anterograde RTK Transport Pathway

“…Given that FGFR3 is seen predominantly in intracellular vesicles under normal conditions, it is worth investigating this phenomenon in the context of RART and FGFR signaling pathways. On the other hand, based on the known utilization of spatially and temporally integrated signaling outputs from multiple RTKs to achieve directed cell migration [81][82][83][84], we speculate that neuronal path-finding and vascular development could involve variation(s) of the RART pathway.…”

Ephs in cancer progression: complexity and context-dependent nature in signaling, angiogenesis and immunity

“…However, in the absence of ligand ephrins, Eph receptor ligand-independent signaling promotes the pro-oncogenic effects. The physical interactions between ephrin and Eph receptors within the same cell, as well as the interaction of Eph receptor with other RTKs, contribute to processes such as proliferation, differentiation, adhesion and migration [ 107 ].…”