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.
Highlights
Cell adhesion to the extracellular matrix regulates many cellular functions, including cell differentiation, proliferation, apoptosis, and migration [1]
Our novel findings are as follows: 1) the function of JSAP1 as a Jun N-terminal kinase (JNK) scaffold is augmented by its binding to focal adhesion kinase (FAK); 2) JSAP1 and p130 Crk-associated substrate (p130Cas) function cooperatively to transmit signaling to JNK and to regulate FAK activity; 3) Jsap1-null ES cells are impaired in FN-induced lamellipodial protrusion formation and membrane ruffling; 4) JSAP1 expression stimulates FN-induced cell migration, and this stimulation depends on the ability of JSAP1 to promote JNK activation; and 5) JSAP1 mRNA expression correlates with the malignant phenotype of brain tumors
The FAK/ p130Cas pathway is believed to be essential for FN-induced JNK activation and cell migration [2, 4, 5, 7,8,9, 15], even though the precise mechanism by which JNK pathway constituents associate with the FAK scaffold is largely unknown
Summary
Cell adhesion to the extracellular matrix regulates many cellular functions, including cell differentiation, proliferation, apoptosis, and migration [1]. These results suggest that JSAP1 expression promotes FN-induced JNK activation by facilitating the FAK/p130Cas pathway.
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