title: Neuregulin mediates F-actin-driven cell migration through inhibition of protein kinase D1 via Rac1 protein.
abstract: Neuregulin (NRG; heregulin) is overexpressed in ∼30% of breast cancers and mediates various processes involved in tumor progression, including tumor cell migration and invasion. Here, we show that NRG mediates its effects on tumor cell migration via PKD1. Downstream of RhoA, PKD1 can prevent directed cell migration through phosphorylation of its substrate SSH1L. NRG exerts its inhibitory effects on PKD1 through Rac1/NADPH oxidase, leading to decreased PKD1 activation loop phosphorylation and decreased activity toward SSH1L. The consequence of PKD1 inhibition by NRG is decreased binding of 14-3-3 to SSH1L, localization of SSH1L to F-actin at the leading edge, and increased cofilin activity, resulting in increased reorganization of the actin cytoskeleton and cell motility. Our data provide a mechanism through which the Rho GTPase Rac1 cross-talks with PKD1 signaling pathways to facilitate directed cell migration.
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Döppler
authors.forename: Ligia I
authors.initials: LI
authors.lastname: Bastea
authors.forename: Tim
authors.initials: T
authors.lastname: Eiseler
authors.forename: Peter
authors.initials: P
authors.lastname: Storz
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002465:Cell Movement; D002633:Chemotaxis; D018450:Disease Progression; D005260:Female; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D020890:Neuregulin-1 / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D014945:Wound Healing; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; D020890:Neuregulin-1; D034741:RNA, Small Interfering; C089212:protein kinase D; D011493:Protein Kinase C; D020830:rac1 GTP-Binding Protein