Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3

摘要: Diacylglycerol (DAG) is a central mediator of signaling pathways that regulate cell proliferation, survival and apoptosis. Therefore, C1 domain, the DAG binding site within protein kinase C (PKC) other effector proteins, considered potential cancer drug target. Derivatives 5-(hydroxymethyl)isophthalic acid are novel group domain ligands with antiproliferative differentiation-inducing effects. Our previous work showed these isophthalate derivatives exhibit elongation-inducing effects in HeLa human cervical cells. In this study we further characterized bis(3-trifluoromethylbenzyl) 5-(hydroxymethyl)isophthalate (HMI-1a3) on proliferation morphology. HMI-1a3-induced elongation was accompanied loss focal adhesions actin stress fibers, exposure to HMI-1a3 induced prominent relocation cofilin-1 into nucleus regardless phenotype. The morphological responses were not modified by pharmacological inhibition or activation PKC, RNAi knock-down specific PKC isoforms, suggesting mediated PKC. Genome-wide gene expression microarray set enrichment analysis suggested that, among others, induces changes small GTPase-mediated pathways. experiments revealed isophthalates bind also domains β2-chimaerin, D (PKD) myotonic dystrophy kinase-related Cdc42-binding (MRCK), which mediators GTPase cytoskeletal reorganization. Pharmacological MRCK, but PKD attenuated elongation, MRCK participates mediating