rin3 is a negative regulator of mast cell responses to scfrin3是负的现金流量表监管机构肥大细胞的反应.pdfVIP

RIN3 Is a Negative Regulator of Mast Cell Responses to SCF 1 2 3 1 Christine Janson , Noriyuki Kasahara , George C. Prendergast , John Colicelli * 1 Molecular Biology Institute, Jonsson Comprehensive Cancer Center, Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America, 2 Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America, 3 Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, United of States of America Abstract Stimulation of the receptor tyrosine kinase KIT by Stem Cell Factor (SCF) triggers activation of RAS and its downstream effectors. Proper KIT activation is essential for the maturation, survival and proliferation of mast cells. In addition, SCF activation of KIT is critical for recruiting mast cells to sites of infection or injury, where they release a mix of pro- inflammatory substances. RIN3, a RAS effector and RAB5-directed guanine nucleotide exchange factor (GEF), is highly expressed and enriched in human mast cells. SCF treatment of mast cells increased the amount of GTP-bound RAB5, and the degree of RAB5 activation correlated with the expression level of RIN3. At the same time, SCF caused the dissociation of a pre-formed complex of RIN3 with BIN2, a membrane bending protein implicated in endocytosis. Silencing of RIN3 increased the rate of SCF-induced KIT internalization, while persistent RIN3 over-expression led to KIT down regulation. These observations strongly support a role for RIN3 in coordinating the early steps of KIT endocytosis. Importantly,