14-3-3ε Couples Protein Kinase A to Semaphorin Signaling and Silences Plexin RasGAP-Mediated Axonal Repulsion

Departments of Neuroscience and Pharmacology and Neuroscience Graduate Program, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Neuron (Impact Factor: 15.05). 04/2012; 74(1):108-21. DOI: 10.1016/j.neuron.2011.12.034
Source: PubMed


The biochemical means through which multiple signaling pathways are integrated in navigating axons is poorly understood. Semaphorins are among the largest families of axon guidance cues and utilize Plexin (Plex) receptors to exert repulsive effects on axon extension. However, Semaphorin repulsion can be silenced by other distinct cues and signaling cascades, raising questions of the logic underlying these events. We now uncover a simple biochemical switch that controls Semaphorin/Plexin repulsive guidance. Plexins are Ras/Rap family GTPase activating proteins (GAPs) and we find that the PlexA GAP domain is phosphorylated by the cAMP-dependent protein kinase (PKA). This PlexA phosphorylation generates a specific binding site for 14-3-3ε, a phospho-binding protein that we find to be necessary for axon guidance. These PKA-mediated Plexin-14-3-3ε interactions prevent PlexA from interacting with its Ras family GTPase substrate and antagonize Semaphorin repulsion. Our results indicate that these interactions switch repulsion to adhesion and identify a point of convergence for multiple guidance molecules.

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    • "Furthermore, endocytosis, receptor phosphorylation, membrane protein shedding, intracellular protein degradation and protein transport have been identified as strategies to control semaphorin signalling at specific times and places in the cell (e.g. Dang et al., 2012; Nawabi et al., 2010; Yang and Terman, 2012; Zhu et al., 2007). "
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    ABSTRACT: Semaphorins are secreted and membrane-associated proteins that regulate many different developmental processes, including neural circuit assembly, bone formation and angiogenesis. Trans and cis interactions between semaphorins and their multimeric receptors trigger intracellular signal transduction networks that regulate cytoskeletal dynamics and influence cell shape, differentiation, motility and survival. Here and in the accompanying poster we provide an overview of the molecular biology of semaphorin signalling within the context of specific cell and developmental processes, highlighting the mechanisms that act to fine-tune, diversify and spatiotemporally control the effects of semaphorins.
    Full-text · Article · Sep 2014 · Development
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    • "Moreover, the cytoplasmic domain of different plexins was found to associate with other putative effector proteins, such as p190Rho- GAP, PDZ-RhoGEFs, MICALs, FARP2 (reviewed by Zhou et al., 2008), and 14.3.3 proteins (Yang and Terman, 2012). "
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    ABSTRACT: Semaphorins are mainly known as guidance signals in development, acting through receptors called Plexins. However, their role in cancer is rapidly emerging in the regulation of tumor angiogenesis, tumor growth, cancer cell invasiveness, and metastatic spreading. Intriguingly, activated plexins can transactivate receptor tyrosine kinases, such as MET, VEGFR2, FGFR2, and ERBB2, and lead to distinctive effects in a cell-context-dependent manner. Moreover, certain semaphorins concomitantly target endothelial and cancer cells, and can achieve remarkable inhibition of angiogenesis and tumor growth, associated with anti-metastatic activity. Altogether, these data validate the identification of semaphorin signals as promising therapeutic targets in cancer.
    Full-text · Article · Aug 2012 · Cancer cell
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    ABSTRACT: Plexin transmembrane receptors and their semaphorin ligands, as well as their co-receptors (Neuropilin, Integrin, VEGFR2, ErbB2, and Met kinase) are emerging as key regulatory proteins in a wide variety of developmental, regenerative, but also pathological processes. The diverse arenas of plexin function are surveyed, including roles in the nervous, cardiovascular, bone and skeletal, and immune systems. Such different settings require considerable specificity among the plexin and semaphorin family members which in turn are accompanied by a variety of cell signaling networks. Underlying the latter are the mechanistic details of the interactions and catalytic events at the molecular level. Very recently, dramatic progress has been made in solving the structures of plexins and of their complexes with associated proteins. This molecular level information is now suggesting detailed mechanisms for the function of both the extracellular as well as the intracellular plexin regions. Specifically, several groups have solved structures for extracellular domains for plexin-A2, -B1, and -C1, many in complex with semaphorin ligands. On the intracellular side, the role of small Rho GTPases has been of particular interest. These directly associate with plexin and stimulate a GTPase activating (GAP) function in the plexin catalytic domain to downregulate Ras GTPases. Structures for the Rho GTPase binding domains have been presented for several plexins, some with Rnd1 bound. The entire intracellular domain structure of plexin-A1, -A3, and -B1 have also been solved alone and in complex with Rac1. However, key aspects of the interplay between GTPases and plexins remain far from clear. The structural information is helping the plexin field to focus on key questions at the protein structural, cellular, as well as organism level that collaboratoria of investigations are likely to answer.
    Full-text · Article · Jun 2012 · Cellular and Molecular Life Sciences CMLS
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