title: JSAP1/JIP3 cooperates with focal adhesion kinase to regulate c-Jun N-terminal kinase and cell migration.
abstract: c-Jun N-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1) (also termed JNK-interacting protein 3; JIP3) is a member of a family of scaffold factors for the mitogen-activated protein kinase (MAPK) cascades, and it also forms a complex with focal adhesion kinase (FAK). Here we demonstrate that JSAP1 serves as a cooperative scaffold for activation of JNK and regulation of cell migration in response to fibronectin (FN) stimulation. JSAP1 mediated an association between FAK and JNK, which was induced by either co-expression of Src or attachment of cells to FN. Complex formation of FAK with JSAP1 and p130 Crk-associated substrate (p130(Cas)) resulted in augmentation of FAK activity and phosphorylation of both JSAP1 and p130(Cas), which required p130(Cas) hyperphosphorylation and was abolished by inhibition of Src. JNK activation by FN was enhanced by JSAP1, which was suppressed by disrupting the FAK/p130(Cas) pathway by expression of a dominant-negative form of p130(Cas) or by inhibiting Src. We also documented the co-localization of JSAP1 with JNK and phosphorylated FAK at the leading edge and stimulation of cell migration by JSAP1 expression, which depended on its JNK binding domain and was suppressed by inhibition of JNK. The level of JSAP1 mRNA correlated with advanced malignancy in brain tumors, unlike other JIPs. We propose that the JSAP1.FAK complex functions cooperatively as a scaffold for the JNK signaling pathway and regulator of cell migration on FN, and we suggest that JSAP1 is also associated with malignancy in brain tumors.
authors.affiliation: Department of Molecular Virology, Cancer Research Institute, Division of Neuroscience, Graduate School of Medical Science, Kanazawa University, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Takino
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.forename: Hisashi
authors.initials: H
authors.lastname: Miyamori
authors.forename: Yumi
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Tokiharu
authors.initials: T
authors.lastname: Sato
authors.forename: Davaakhuu
authors.initials: D
authors.lastname: Gantulga
authors.forename: Katsuji
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Yamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485750:MAPK8IP3 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases