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      Rin-like, a novel regulator of endocytosis, acts as guanine nucleotide exchange factor for Rab5a and Rab22


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          RIN proteins serve as guanine nucleotide exchange factors for Rab5a. They are characterized by the presence of a RIN homology domain and a C-terminal Vps9 domain. Currently three family members have been described and analyzed. Here we report the identification of a novel RIN family member, Rin-like (Rinl), that represents a new interaction partner of the receptor tyrosine kinase MuSK, which is an essential key regulator of neuromuscular synapse development. Rinl is localized to neuromuscular synapses but shows the highest expression in thymus and spleen. Rinl preferentially binds to nucleotide-free Rab5a and catalyzes the exchange of GDP for GTP. Moreover, Rinl also binds GDP-bound Rab22 and increases the GDP/GTP exchange implicating Rinl in endocytotic processes regulated by Rab5a and Rab22. Interestingly, Rinl shows a higher catalytic rate for Rab22 compared to Rab5a. Rinl is closely associated with the cytoskeleton and thus contributes to the spatial control of Rab5a and Rab22 signaling at actin-positive compartments. Most importantly, overexpression of Rinl affects fluid-phase as well as EGFR endocytosis.

          Research highlights

          ► Rinl is a novel member of the RIN protein family and specifically binds MuSK. ► Rinl catalyzes the nucleotide exchange on Rab5a and Rab22. ► Rinl shows a higher catalytic activity for Rab22 than Rab5a. ► Rinl regulates the localization of Rab5a and Rab22 to actin-positive membrane ruffles. ► Overexpression of Rinl increases both fluid-phase and receptor-mediated endocytosis.

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          Most cited references45

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          High-efficiency transformation of mammalian cells by plasmid DNA.

          We describe a simple calcium phosphate transfection protocol and neo marker vectors that achieve highly efficient transformation of mammalian cells. In this protocol, the calcium phosphate-DNA complex is formed gradually in the medium during incubation with cells and precipitates on the cells. The crucial factors for obtaining efficient transformation are the pH (6.95) of the buffer used for the calcium phosphate precipitation, the CO2 level (3%) during the incubation of the DNA with the cells, and the amount (20 to 30 micrograms) and the form (circular) of DNA. In sharp contrast to the results with circular DNA, linear DNA is almost inactive. Under these conditions, 50% of mouse L(A9) cells can be stably transformed with pcDneo, a simian virus 40-based neo (neomycin resistance) marker vector. The NIH3T3, C127, CV1, BHK, CHO, and HeLa cell lines were transformed at efficiencies of 10 to 50% with this vector and the neo marker-incorporated pcD vectors that were used for the construction and transduction of cDNA expression libraries as well as for the expression of cloned cDNA in mammalian cells.
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            Lrp4 is a receptor for Agrin and forms a complex with MuSK.

            Neuromuscular synapse formation requires a complex exchange of signals between motor neurons and skeletal muscle fibers, leading to the accumulation of postsynaptic proteins, including acetylcholine receptors in the muscle membrane and specialized release sites, or active zones in the presynaptic nerve terminal. MuSK, a receptor tyrosine kinase that is expressed in skeletal muscle, and Agrin, a motor neuron-derived ligand that stimulates MuSK phosphorylation, play critical roles in synaptic differentiation, as synapses do not form in their absence, and mutations in MuSK or downstream effectors are a major cause of a group of neuromuscular disorders, termed congenital myasthenic syndromes (CMS). How Agrin activates MuSK and stimulates synaptic differentiation is not known and remains a fundamental gap in our understanding of signaling at neuromuscular synapses. Here, we report that Lrp4, a member of the LDLR family, is a receptor for Agrin, forms a complex with MuSK, and mediates MuSK activation by Agrin.
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              The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo.

              Formation of neuromuscular synapses requires a series of inductive interactions between growing motor axons and differentiating muscle cells, culminating in the precise juxtaposition of a highly specialized nerve terminal with a complex molecular structure on the postsynaptic muscle surface. The receptors and signaling pathways mediating these inductive interactions are not known. We have generated mice with a targeted disruption of the gene encoding MuSK, a receptor tyrosine kinase selectively localized to the postsynaptic muscle surface. Neuromuscular synapses do not form in these mice, suggesting a failure in the induction of synapse formation. Together with the results of an accompanying manuscript, our findings indicate that MuSK responds to a critical nerve-derived signal (agrin), and in turn activates signaling cascades responsible for all aspects of synapse formation, including organization of the postsynaptic membrane, synapse-specific transcription, and presynaptic differentiation.

                Author and article information

                Biochim Biophys Acta
                Biochim. Biophys. Acta
                Biochimica et Biophysica Acta
                Elsevier Pub. Co
                June 2011
                June 2011
                : 1813
                : 6
                : 1198-1210
                [a ]Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria
                [b ]Department of Physiological Chemistry, UMC Utrecht, 3584 CG Utrecht, The Netherlands
                Author notes
                [* ]Corresponding author at: Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090 Vienna, Austria. Tel.: +43 1 4016034350; fax: +43 1 40160934093. ruth.herbst@ 123456meduniwien.ac.at
                © 2011 Elsevier B.V.

                This document may be redistributed and reused, subject to certain conditions.

                : 5 November 2010
                : 8 March 2011
                : 10 March 2011

                receptor tyrosine kinase,gef, guanine nucleotide exchange factor,rt-pcr, reverse transcriptase polymerase chain reaction,musk, muscle specific kinase,sh2, src homology 2,gst, glutathione s-transferase,bgt, bungarotoxin,musk,achr, acetylcholine receptor,hrp, horseradish peroxidase,gfp, green fluorescent protein,endocytosis,rtk, receptor tyrosine kinase,rab5,gef,egfr, epidermal growth factor receptor


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