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Using cell culturing system, mouse model and patient samples, this work is the first to demonstrate the essential roles of Icmt in ovarian cancer via Ras signaling, particularly on its response to chemotherapy.
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Apoptosis, but not autophagy, that is induced via p21-activated BNIP3 expression accounts for the efficacy of ICMT inhibition in sensitive pancreatic cancer cells in both in vitro and in vivo models. In contrast, cells resistant to ICMT inhibition demonstrated no mitochondria dysfunction or p21 signaling changes under ICMT suppression
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ICMT catalyzed carboxylmethylation is critical for RAB4A activation and interaction with effectors, its localization to endosomes and recycling vesicles, and hence important for RAB4A-dependent integrin beta3 recycling to plasma membrane.
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ICMT function is critical for the tumorigenesis capacity of naturally occurring mutant KRAS human cancer cells.
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simultaneous inhibition of BCR-ABL1 and Icmt may represent a potential therapeutic strategy for CML.
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impact of Icmt on tumorigenic processes
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Silencing ICMT in osteosarcoma cells decreased Notch1 signaling in response to stimulation with cell-surface ligands.
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a role for isoprenylcysteine carboxylmethyltransferase in cell migration and adhesion.
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modulation of pcCMT activity in retinoic acid (RA)-treated SH-SY5Y neuroblastoma cells
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ICMTase is a critical component of the redox-sensitive VCAM-1-selective signaling pathway and appears to activate a discrete inflammatory signaling pathway, at least in part, through the methylation of Rac1 in endothelial cells.
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findings suggest that inhibition of isoprenylcysteine-O-carboxyl methyltransferase (ICMT) causes endothelial cell apoptosis by attenuation of Ras GTPase methylation and activation and its downstream antiapoptotic signaling pathway.
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These studies identify isoprenylcysteine carboxyl methyltransferase as a potential target for reducing the growth of K-Ras- and B-Raf-induced malignancies.
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ICMT inhibition induces endothelial cell apoptosis through GRP94
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Icmt traverses the Eendoplasmic reticulum membrane eight times, with both N and C termini disposed toward the cytosol and with a helix-turn-helix structure comprising transmembrane (TM) segments 7 and 8.
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Inhibition of isoprenylcysteine carboxylmethyltransferase (Icmt) decreases activation of RhoA and Rac1, and in the absence of Icmt activity, addition of exogenous RhoA or Rac1 partially rescues directed and random migration, respectively.
