title: c-Jun N-terminal kinase 2 (JNK2) enhances cell migration through epidermal growth factor substrate 8 (EPS8).
abstract: Membrane-bound receptors induce biochemical signals to remodel the actin cytoskeleton and mediate cell motility. In association with receptor tyrosine kinases, several downstream mitogen-induced kinases facilitate cell migration. Here, we show a role for c-Jun N-terminal kinase 2 (JNK2) in promoting mammary cancer cell migration through inhibition of epidermal growth factor substrate 8 (EPS8) expression, a key regulator of EGF receptor (R) signaling and trafficking. Using jnk2(-/-) mice, we found that EPS8 expression is higher in polyoma middle T antigen (PyVMT)jnk2(-/-) mammary tumors and jnk2(-/-) mammary glands compared with the respective jnk2(+/+) controls. The inverse relationship between the jnk2 and eps8 expression was also associated with cancer progression in that patients with basal-type breast tumors expressing high jnk2 and low eps8 experienced poor disease-free survival. In mammary tumor cell lines, the absence of jnk2 greatly reduces cell migration that is rescued by EPS8 knockdown. Subsequent studies show that JNK2 enhances formation of the EPS8-Abi-1-Sos-1 complex to augment EGFR activation of Akt and ERK, whereas the absence of JNK2 promotes ESP8/RN-Tre association to inhibit endocytotic trafficking of the EGFR. Together, these studies unveil a critical role for JNK2 and EPS8 in receptor tyrosine kinase signaling and trafficking to convey distinctly different effects on cell migration.
authors.affiliation: From the College of Pharmacy, Division of Pharmacology/Toxicology, and Center for Molecular and Cellular Toxicology, and.
authors.forename: Shreya
authors.initials: S
authors.lastname: Mitra
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Cantrell
authors.forename: Carla Lynn
authors.initials: CL
authors.lastname: Van den Berg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000502:physiology*; D018450:Disease Progression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D015674:Mammary Neoplasms, Animal / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000502:physiology*; D021381:Protein Transport
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C489989:EPS8 protein, human; C083430:Eps8 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D048056:Mitogen-Activated Protein Kinase 9