They comprise a tandem catalytic Dbl-homology (DH) domain and a regulatory pleckstrin homology (PH) domain, together forming the functional GEF unit ( Fig. 1). The Trio family protein GEF domains catalyze exchange of GDP for GTP on specific Rho family GTPases, master regulators of the cytoskeleton ( Jaffe and Hall, 2005). An outstanding question in the field is how small differences between Trio and kalirin, or the usage of different isoforms, drives Trio family proteins to perform their vast set of distinct tasks within a cell. Finally, different isoforms of each vary in abundance in different contexts ( McPherson et al., 2005, McPherson et al., 2002). Additionally, Trio is abundant in the developing brain ( Ma et al., 2005), while kalirin predominates in the brain from postnatal development through adulthood ( Ma et al., 2001). Trio is ubiquitously expressed, whereas kalirin is most highly expressed in the nervous system ( Miller et al., 2013 Debant et al., 1996 Alam et al., 1997 Wu et al., 2013). While Trio and kalirin have nearly identical domain structure, they have different tissue-specific and temporal expression profiles ( Miller et al., 2013). Amino acid numbers are marked on dotted line for scale.
Only the isoforms mentioned in this review are shown in the figure for a more comprehensive list, see Steven et al., (1998), McPherson et al. Trio, kalirin and UNC-73 are alternatively spliced to generate multiple isoforms. The additional accessory domains vary slightly between species, but include: a Sec14 domain, nine spectrin repeats (SR1–SR9), one or two Src homology 3 (SH3) domains, and zero or one immunoglobulin-like (Ig) and fibronectin-like (Fn) domains ( Debant et al., 1996 Alam et al., 1997 Steven et al., 1998 Awasaki et al., 2000). The vertebrate members, Trio and kalirin, also contain an additional putative kinase domain. All full-length (FL) Trio family proteins (Trio FL, kalirin FL/Kal12, UNC-73A, and Drosophila Trio) contain two catalytic GEF units (shown in blue in the figure) composed of tandem Dbl homology (DH) and pleckstrin homology (PH) domains. Trio family proteins are large multi-domain proteins that contain up to three catalytic domains and multiple accessory domains. How are the different catalytic activities balanced within Trio proteins? How do the accessory domains in Trio proteins contribute to Trio function, and how does the primary function of Trio proteins differ based on its interactions with cellular binding partners?īox 1. Recent studies have linked mutations in the human genes TRIO and kalirin ( KALRN) to neurological diseases ( Paskus et al., 2020) and cancers ( Schmidt and Debant, 2014), highlighting the need to understand the primary functions of Trio family proteins and underscoring the outstanding questions in the field. These diverse roles are achieved through Trio protein interactions with membrane receptors, cytoskeleton-interacting proteins, lipids, endocytic machinery, kinases and Rho family GTPases in the cell ( Fig. 1). Trio family proteins are key regulators of cell motility and morphogenesis, tissue development, and protein trafficking and secretion in numerous biological contexts, including their prominent roles in developing nervous systems. 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. 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.
ORGANIZED TRIO ACTIVATION KEY SERIES
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. Recent discoveries have linked Trio and kalirin to human disease, including neurological disorders and cancer. Trio proteins are key regulators of cell morphogenesis and migration, tissue organization, and secretion and protein trafficking in many biological contexts. 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.
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