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Review
. 2021 Feb 10;134(3):jcs248393.
doi: 10.1242/jcs.248393.

Trio family proteins as regulators of cell migration and morphogenesis in development and disease - mechanisms and cellular contexts

Josie E Bircher  1 , Anthony J Koleske  1
Affiliations
Review

Trio family proteins as regulators of cell migration and morphogenesis in development and disease - mechanisms and cellular contexts

Josie E Bircher et al. J Cell Sci. .

Erratum in

Abstract

The well-studied members of the Trio family of proteins are Trio and kalirin in vertebrates, UNC-73 in Caenorhabditis elegans and Trio in Drosophila Trio proteins are key regulators of cell morphogenesis and migration, tissue organization, and secretion and protein trafficking in many biological contexts. Recent discoveries have linked Trio and kalirin to human disease, including neurological disorders and cancer. The genes for Trio family proteins encode a series of large multidomain proteins with up to three catalytic activities and multiple scaffolding and protein-protein interaction domains. As such, Trio family proteins engage a wide array of cell surface receptors, substrates and interaction partners to coordinate changes in cytoskeletal regulatory and protein trafficking pathways. We provide a comprehensive review of the specific mechanisms by which Trio family proteins carry out their functions in cells, highlight the biological and cellular contexts in which they occur, and relate how alterations in these functions contribute to human disease.

Keywords: Cell morphogenesis; Cytoskeleton; Neurodevelopmental disorders; Rho GTPase; Signal transduction; Trio family.

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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Trio family proteins integrate signaling from a wide array of interaction partners to impact cell behaviors. Trio family proteins relay signaling with adhesion receptors, lipids, kinases, secretory and endocytic machinery, cytoskeleton-associated proteins, and guidance receptors to regulate secretion and trafficking, tissue organization, and cell migration and morphogenesis. Much, but not all, of this signaling is achieved through Trio catalytic activities on Rho family GTPases. Domains of the Trio proteins: SR, spectrin repeats; DH, Dbl homology; PH, pleckstrin homology; GEF, guanine nucleotide exchange factor; SH3, Src homology 3; Ig, immunoglobulin-like.
Fig. 2.
Fig. 2.
Trio family proteins respond to axon guidance cues through guidance receptors. Trio family proteins respond to both attractive and repulsive guidance cues, which induces either axon outgrowth or growth cone collapse. (1) In the presence of netrin, the netrin receptor DCC interacts with Trio – it is unknown if this interaction is direct. This interaction results in a Trio GEF1-mediated activation of Rac1, which is necessary for axon outgrowth. (2) Netrin stimulation also induces phosphorylation of Trio at Y2622 by the kinase Fyn (yellow star), which leads to increased surface levels of DCC. While the roles of Trio in pathways (1) and (2) have not been explicitly connected, Trio-dependent stimulation of DCC at the surface (2) likely constitutes a positive feedback loop to amplify more netrin-DCC signaling in (1). (3) In contrast, binding of Slit to the Robo/SAX-3 receptors results in Trio GEF2-mediated RhoA activation, which causes growth cone collapse.
Fig. 3.
Fig. 3.
Trio family proteins utilize both GEF domains to promote endothelial adherens junctions. Trio family proteins are important for maintaining adherens junction (AJ) integrity between endothelial cells. AJ formation and integrity are impacted by interactions with other types of cells (mural cells), laminar flow, and the basal remodeling of AJs. (A) Neural (N)-cadherin ligation between a mural cell and an epithelial cell induces Trio GEF1 to activate Rac1, increasing vascular endothelial (VE)-cadherin recruitment to AJs between neighboring endothelial cells. How N-cadherin signals to Trio, and how Rac1 activation increases VE-cadherin recruitment to AJs in this context, are unknown. N-cadherin ligation also increases Trio GEF2-mediated RhoA activation, increasing intracellular tension, and serving as a positive-feedback loop to reinforce the activity of Trio GEF1. It is unclear how N-cadherin signals to Trio GEF2 and how intracellular tension influences Trio GEF1 activity. (B) Notch1 is cleaved upon interaction with ligand DLL4 under conditions of laminar flow, which allows the Notch1 transmembrane domain (TMD) to colocalize with protein-tyrosine phosphatase (LAR), VE-cadherin and Trio. By an unknown mechanism, assembly of this Notch1–LAR–VE-cadherin–Trio complex induces Trio GEF1-mediated activation of Rac1, which strengthens AJs. (C) In basal conditions, AJs are constantly remodeled. Ligation of VE-cadherins in the formation of new AJs recruits Trio GEF1 to nascent AJs and subsequent local Trio GEF1-mediated Rac1 activation to strengthen nascent adhesions. Trio binds directly to VE-cadherin so this interaction likely drives Trio recruitment to AJs.
Fig. 4.
Fig. 4.
Trio family protein mutations and phosphorylation sites. Specific locations of Trio mutations associated with various neurodevelopmental disorders. Interestingly, mutations to Trio cluster in distinct regions of the gene, many clustering around the area encoding the first GEF domain. Solid lines indicate missense mutations; dotted lines indicate nonsense mutations. For a full list of known mutations, see Table S1. BPD, bipolar disorder; ASD, autism spectrum disorder; ID, intellectual disability; DD, developmental delay; SCZ, schizophrenia. Domains of Trio are as in Fig. 1.
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References

    1. Adamowicz, M., Radlwimmer, B., Rieker, R. J., Mertens, D., Schwarzbach, M., Schraml, P., Benner, A., Lichter, P., Mechtersheimer, G. and Joos, S. (2006). Frequent amplifications and abundant expression of Trio, NKD2, and IRX2 in soft tissue sarcomas. Genes Chromosomes Cancer 45, 829-838. 10.1002/gcc.20343 - DOI - PubMed
    1. Alam, M. R., Johnson, R. C., Darlington, D. N., Hand, T. A., Mains, R. E. and Eipper, B. A. (1997). Kalirin, a cytosolic protein with spectrin-like and GDP/GTP exchange factor-like domains that interacts with peptidylglycine α-amidating monooxygenase, an integral membrane peptide-processing enzyme. J. Biol. Chem. 272, 12667-12675. 10.1074/jbc.272.19.12667 - DOI - PubMed
    1. Alexander, M., Selman, G., Seetharaman, A., Chan, K. K. M., D'Souza, S. A., Byrne, A. B. and Roy, P. J. (2010). MADD-2, a homolog of the Opitz syndrome protein MID1, regulates guidance to the midline through UNC-40 in Caenorhabditis elegans. Dev. Cell 18, 961-972. 10.1016/j.devcel.2010.05.016 - DOI - PubMed
    1. Awasaki, T., Saito, M., Sone, M., Suzuki, E., Sakai, R., Ito, K. and Hama, C. (2000). The Drosophila trio plays an essential role in patterning of axons by regulating their directional extension. Neuron 26, 119-131. 10.1016/S0896-6273(00)81143-5 - DOI - PubMed
    1. Backer, S., Lokmane, L., Landragin, C., Deck, M., Garel, S. and Bloch-Gallego, E. (2018). Trio GEF mediates RhoA activation downstream of Slit2 and coordinates telencephalic wiring. Development 145, dev153692 10.1242/dev.153692 - DOI - PubMed

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