The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proc Natl Acad Sci U S A 2002 Sep 17;99(19):12085-90
Date
08/28/2002Pubmed ID
12196628Pubmed Central ID
PMC129402DOI
10.1073/pnas.142433199Scopus ID
2-s2.0-0037126064 (requires institutional sign-in at Scopus site) 153 CitationsAbstract
Semaphorins are axon guidance molecules that signal through the plexin family of receptors. Semaphorins also play a role in other processes such as immune regulation and tumorigenesis. However, the molecular signaling mechanisms downstream of plexin receptors have not been elucidated. Semaphorin 4D is the ligand for the plexin-B1 receptor and stimulation of the plexin-B1 receptor activates the small GTPase RhoA. Using the intracellular domain of plexin-B1 as an affinity ligand, two Rho-specific guanine nucleotide exchange factors, leukemia-associated Rho GEF (LARG; GEF, guanine nucleotide exchange factors) and PSD-95/Dlg/ZO-1 homology (PDZ)-RhoGEF, were isolated from mouse brain as plexin-B1-specific interacting proteins. LARG and PDZ-RhoGEF contain several functional domains, including a PDZ domain. Biochemical characterizations showed that the PDZ domain of LARG is directly involved in the interaction with the carboxy-terminal sequence of plexin-B1. Mutation of either the PDZ domain in LARG or the PDZ binding site in plexin-B1 eliminates the interaction. The interaction between plexin-B1 and LARG is specific for the PDZ domain of LARG and LARG does not interact with plexin-A1. A LARG-interaction defective mutant of the plexin-B1 receptor was created and was unable to stimulate RhoA activation. The data in this report suggest that LARG plays a critical role in plexin-B1 signaling to stimulate Rho activation and cytoskeletal reorganization.
Author List
Aurandt J, Vikis HG, Gutkind JS, Ahn N, Guan KLMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Base Sequence
Brain
Cell Line
DNA, Recombinant
Guanine Nucleotide Exchange Factors
Humans
In Vitro Techniques
Mass Spectrometry
Mice
Mutagenesis, Site-Directed
Nerve Tissue Proteins
Receptors, Cell Surface
Recombinant Proteins
Rho Guanine Nucleotide Exchange Factors
Signal Transduction
rhoA GTP-Binding Protein