Regulation of Two JunD Isoforms by Jun N-terminal Kinases

Abstract

The JunD transcription factor is one member of the Jun family of proteins that also includes c-Jun and JunB. Although c-Jun can function to promote cell proliferation and can cooperate with other oncogenes to transform cells, JunD slows proliferation of fibroblasts and antagonizes transformation by activated ras. Two isoforms of JunD, a full-length isoform containing 341 amino acids (JunD-FL) and a truncated isoform lacking 48 amino acids at the N terminus (⌬JunD), are generated through utilization of two translation start sites within a single mRNA. Here we show that both isoforms of JunD are phosphorylated by Jun N-terminal kinases (JNKs) at three identical residues and that both contain a docking domain that specifically binds JNKs. The JunD-FL isoform binds to and is phosphorylated by JNK more efficiently than ⌬JunD in vitro; correspondingly, JunD-FL is a more potent transcriptional activator than ⌬JunD. Although increased JNK signaling can activate both JunD isoforms, mutating either the JNK docking domain or the target JNK phosphorylation sites blocks this activation. These results identify two distinct isoforms of JunD with differential responses to JNK signaling pathways.

Tobacco Smoke Control of Mucin Production in Lung Cells Requires Oxygen Radicals AP-1 and JNK

“…Subsequent reports have indicated, however, that all three are legitimate JNK substrates. Phosphoacceptor sites have been identified on the JunB protein at Thr-102 and Thr-104 (39), whereas a JNK docking site has been identified on the JunD protein at Leu-57/Leu-59 (40). Consistent with supershift data suggesting roles for both JunD and Fra-2 in the induction of mucin by smoke, our results showed that mucin induction was dependent on both JNK and ERK.…”

Multiple facets of junD gene expression are atypical among AP-1 family members

“…As highlighted in Figure 1, JunD is phosphorylated by JNK at serines 90 and 100, which are conserved phosphorylation sites in c-Jun, and at threonine 117 (Yazgan and Pfarr, 2002). Downregulation of JNK by estrogen decreases JunD phosphorylation, which in turn decreases expression of the junD mRNA.…”

“…JunD activity is positively regulated by mitogen activated protein kinase Phosphorylation of JunD at the N-terminus by mitogen activated protein kinase JNK positively regulates trans-activation activity (Adler et al, 1994;Yazgan and Pfarr, 2002). As highlighted in Figure 1, JunD is phosphorylated by JNK at serines 90 and 100, which are conserved phosphorylation sites in c-Jun, and at threonine 117 (Yazgan and Pfarr, 2002).…”

JunD is a profibrogenic transcription factor regulated by Jun N-terminal kinase-independent phosphorylation

“…Ser100 of JunD is a target of JNK-dependent phosphorylation. 19 Overexpression of dominant-negative JNK2 or the JIP1 JNK-binding domain (JIP1 aa127-282 functions as a repressor of JNK1, -2, and -3) 21 did not inhibit TIMP-1 promoter activity (Fig. 7A-B).…”

“…18,19 The N-terminus of JunD contains 3 MAPK-regulated phospho-acceptor sites (Ser90, Ser100, and Thr117) that are phosphorylated in response to ERK1/2 and JNK activation. 14,20 To determine if HSCs support phosphorylation of JunD, human LX-2 HSCs were transfected with the JunD expression vector.…”