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The Trio family of guanine-nucleotide-exchange factors: regulators of axon guidance

Jack Bateman and David Van Vactor*

Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA



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  		Fig. 1. The Trio family. Members identified in vertebrates (Trio and Kalirin), C. elegans (UNC-73) and Drosophila share a series of N-terminal spectrin-like repeats, two GEF domains consisting of a DH domain coupled to a pleckstrin homology (PH) domain, and an SH3 domain located between the two GEF domains. The C-terminal of the molecule differs in all members identified thus far; human Trio encodes a second SH3 domain, an Ig-like domain and a serine/threonine kinase (STK) domain, kalirin encodes two Ig-like repeats and an STK domain, UNC-73 possesses an Ig-like repeat and a fibronectin-like repeat (FNIII), and Drosophila Trio terminates immediately following the C-terminal PH domain. In addition to the molecules depicted, several alternatively spliced variants have been described for kalirin and UNC-73.

 


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  		Fig. 2. Potential interactions in Trio signal transduction. The figure represents a generic Trio family member and incorporates biochemical and genetic data from different organisms. In response to upstream cues (possibly through localization by filamin or LAR-family RPTPs), Trio activates the Rac pathway (red) and/or the Rho pathway (blue) through its two GEF domains. GTP-bound Rac, in cooperation with membrane-localized Nck/Dock, can bind and activate PAK, leading to phosphorylation of substrates that affect the actin cytoskeleton, including inhibitory phosphorylation of myosin light chain kinase (MLC kinase). Theoretically, GTP-bound Rho might bind to and activate Rho-associated kinase (ROK), causing inhibitory phosphorylation and inactivation of MLC phosphatase (MLC PTPase) and subsequent changes in cytoskeletal dynamics. GEF1 also activates RhoG in vertebrates, which subsequently activates Rac and Cdc42 signaling pathways. In invertebrates, GEF1 activates the Rac-like GTPase MIG-2, which signals through unknown effectors. A region of the spectrin repeats of kalirin interacts with PAM and may regulate receptor internalization. Genetic interactions from Drosophila suggest that Trio functions with components of the Abl pathway (including Fax and Ena), but the biochemical nature of this interaction is unclear. Putative binding partners for the SH3 domain and regions within the C-terminal variable region (shown as an Ig/kinase as in human Trio) are as yet poorly understood.

 

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© The Company of Biologists Ltd 2001