title: A novel role for atypical MAPK kinase ERK3 in regulating breast cancer cell morphology and migration.
abstract: ERK3 is an atypical Mitogen-activated protein kinase (MAPK6). Despite the fact that the Erk3 gene was originally identified in 1991, its function is still unknown. MK5 (MAP kinase- activated protein kinase 5) also called PRAK is the only known substrate for ERK3. Recently, it was found that group I p21 protein activated kinases (PAKs) are critical effectors of ERK3. PAKs link Rho family of GTPases to actin cytoskeletal dynamics and are known to be involved in the regulation of cell adhesion and migration. In this study we demonstrate that ERK3 protein levels are elevated as MDA-MB-231 breast cancer cells adhere to collagen I which is concomitant with changes in cellular morphology where cells become less well spread following nascent adhesion formation. During this early cellular adhesion event we observe that the cells retain protrusive activity while reducing overall cellular area. Interestingly exogenous expression of ERK3 delivers a comparable reduction in cell spread area, while depletion of ERK3 expression increases cell spread area. Importantly, we have detected a novel specific endogenous ERK3 localization at the cell periphery. Furthermore we find that ERK3 overexpressing cells exhibit a rounded morphology and increased cell migration speed. Surprisingly, exogenous expression of a kinase inactive mutant of ERK3 phenocopies ERK3 overexpression, suggesting a novel kinase independent function for ERK3. Taken together our data suggest that as cells initiate adhesion to matrix increasing levels of ERK3 at the cell periphery are required to orchestrate cell morphology changes which can then drive migratory behavior.
authors.affiliation: a Department of Pharmacy ; UiT The Arctic University of Norway ; Tromsø , Norway.
authors.forename: Rania
authors.initials: R
authors.lastname: Al-Mahdi
authors.affiliation: b Division of Cancer Studies; New Hunts House ; Guy's Campus; King's College London ; London , UK.
authors.forename: Nouf
authors.initials: N
authors.lastname: Babteen
authors.affiliation: b Division of Cancer Studies; New Hunts House ; Guy's Campus; King's College London ; London , UK.
authors.forename: Kiruthikah
authors.initials: K
authors.lastname: Thillai
authors.affiliation: c Randall Division for Cell and Molecular Biophysics and Cardiovascular Division; King's College London ; London , UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Holt
authors.affiliation: a Department of Pharmacy ; UiT The Arctic University of Norway ; Tromsø , Norway.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Johansen
authors.affiliation: a Department of Pharmacy ; UiT The Arctic University of Norway ; Tromsø , Norway.
authors.forename: Hilde Ljones
authors.initials: HL
authors.lastname: Wetting
authors.affiliation: a Department of Pharmacy ; UiT The Arctic University of Norway ; Tromsø , Norway.
authors.forename: Ole-Morten
authors.initials: OM
authors.lastname: Seternes
authors.affiliation: b Division of Cancer Studies; New Hunts House ; Guy's Campus; King's College London ; London , UK.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Wells
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D048053:Mitogen-Activated Protein Kinase 6 / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C111049:MAP-kinase-activated kinase 5; D017346:Protein Serine-Threonine Kinases; D048053:Mitogen-Activated Protein Kinase 6
keywords: ERK3; actin filaments; cell adhesion; cell motility; cell protrusion; cell-cell adhesion; mitogen-activated protein kinase 6