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	Shreya Mitra, Ju-Seog Lee, Michael Cantrell, Carla Lynn Van den Berg
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 286 Issue 17 Pg. 15287-97 (Apr 29 2011) ISSN: 1083-351X [Electronic] United States
PMID	21357683 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Adaptor Proteins, Signal Transducing Cytoskeletal Proteins EPS8 protein, human Eps8 protein, mouse Intracellular Signaling Peptides and Proteins Mitogen-Activated Protein Kinase 9
Topics	Adaptor Proteins, Signal Transducing (physiology) Animals Breast Neoplasms (pathology) Cell Movement Cytoskeletal Proteins (physiology) Disease Progression Humans Intracellular Signaling Peptides and Proteins (physiology) Mammary Neoplasms, Animal (pathology) Mice Mice, Knockout Mitogen-Activated Protein Kinase 9 (physiology) Protein Transport

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