title: CNK3 and IPCEF1 produce a single protein that is required for HGF dependent Arf6 activation and migration.
abstract: Epithelial cells are largely immotile under normal circumstances, but become motile during development, repair of tissue damage and during cancer metastasis. Numerous growth factors act to initiate epithelial cell movements. Hepatocyte growth factor (HGF) induces many epithelial cell lines to begin crawling. A number of small GTPases act downstream of HGF to alter cell shape and promote movement. Arf6 is one of these GTPases that can alter the cortical actin cytoskeleton and promote epithelial movement. Activation of Arf6 in MDCK cells by its guanine nucleotide exchange factor cytohesin 2/ARNO produces a scattering response strikingly reminiscent of the action of HGF. We have previously shown that IPCEF1, a scaffold that binds to cytohesin 2, is required for cytohesin-induced scattering. We report here that IPCEF1 is actually the C-terminal half of CNK3. CNKs are scaffolds involved in signal transduction downstream of Ras. We have found that both MDCK and CaCo-2 cells express a fused CNK3/IPCEF1 protein. Knockdown of this protein impairs HGF-induced Arf6 activation and migration in response to HGF treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Myriam A
authors.initials: MA
authors.lastname: Attar
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Salem
authors.forename: Heather S
authors.initials: HS
authors.lastname: Pursel
authors.forename: Lorraine C
authors.initials: LC
authors.lastname: Santy
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D004285:Dogs; D005786:Gene Expression Regulation / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins
chemical_list: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; D002352:Carrier Proteins; D017228:Hepatocyte Growth Factor; D008565:Membrane Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C496471:CNKSR3 protein, human; C550843:IPCEF1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C000715348:ARF6 protein, human