Integration of transforming growth factor beta and RAS signaling silences a RAB5 guanine nucleotide exchange factor and enhances growth factor-directed cell migration.
Transforming growth factor beta (TGF-beta) receptor (TbetaR) signaling contributes to normal development as well as tumorigenesis. Here we report that RIN1, a RAB5 guanine nucleotide exchange factor (GEF) and down regulator of receptor tyrosine kinases (RTKs), promotes TbetaR signaling through enhanced endocytosis. TbetaR activation induces SNAI1 (Snail), a transcription repressor that reduces RIN1 expression, providing a negative feedback mechanism to control TbetaR trafficking and downstream signaling. Persistent RAS signaling disrupts this equilibrium by stabilizing SNAI1 protein, resulting in strong silencing of RIN1 and stabilization of RTKs. TGF-beta-induced RIN1 silencing in breast cancer cells prolonged sensitivity to hepatocyte growth factor, a ligand for the MET-type RTK, and enhanced growth factor-directed cell motility. We conclude that in some tumor cells TbetaR and RAS signals are integrated through the silencing of RIN1, leading to a reduction in RAB5-mediated endocytosis. These findings shed new light on the basis for distinct interpretations of TGF-beta signaling by normal versus transformed cells.
Hu
Hailiang
H
Department of Biological Chemistry, Jonsson Comprehensive Cancer Center and Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Milstein
Marc
M
Bliss
Joanne M
JM
Thai
Minh
M
Malhotra
Gautam
G
Huynh
Lucia C
LC
Colicelli
John
J
D045744:Cell Line, Tumor; D002465:Cell Movement; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D017930:Genes, Reporter; D020662:Guanine Nucleotide Exchange Factors / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; C108382:RABGEF1 protein, human; C092117:RIN1 protein, human; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D066246:ErbB Receptors; D018631:ras Proteins