Impaired dynamin 2 function leads to increased AP-1 transcriptional activity through the JNK/c-Jun pathway

Abstract

Activation of AP-1 transcription factors, composed of the Jun and Fos proteins, regulates cellular fates, such as proliferation, differentiation or apoptosis. Among other stimuli, the AP-1 pathway can be initiated by extracellular ligands, such as growth factors or cytokines, which undergo internalization in complex with their receptors. Endocytosis has been implicated in the regulation of several signaling pathways; however its possible impact on AP-1 signaling remains unknown. Here we show that inhibition of dynamin 2 (Dyn2), a major regulator of endocytic internalization, strongly stimulates the AP-1 pathway. Specifically, expression of a dominant-negative Dyn2 K44A mutant increases the total levels of c-Jun, its phosphorylation on Ser63/73 and transcription of AP-1 target genes. Interestingly, DNM2 mutations implicated in human neurological disorders exhibit similar effects on AP-1 signaling. Mechanistically, Dyn2 K44A induces AP-1 by increasing phosphorylation of several receptor tyrosine kinases. Their activation is required to initiate a Src- and JNK-dependent signaling cascade converging on c-Jun and stimulating expression of AP-1 target genes. Cumulatively, our data uncover a link between the Dyn2 function and JNK signaling which leads to AP-1 induction.

Low Dose Cadmium Inhibits Proliferation of Human Renal Mesangial Cells via Activation of the JNK Pathway

“…Cd may affect multiple cellular processes including proliferation [20]. The effect of low dose Cd on the proliferation of HRMCs was examined by MTT assay and cell counting.…”

Prostate tumor overexpressed-1, in conjunction with human papillomavirus status, predicts outcome in early-stage human laryngeal squamous cell carcinoma

“…C-jun is a major transcriptional factors of the AP-1 complex and regulate a variety of cellular fates, including proliferation, differentiation and apoptosis [19]. The role of AP1 complexes in promoting cancer cell invasion and metastasis is well established [20, 21].…”

Aldehyde Dehydrogenase-2 Attenuates Myocardial Remodeling and Contractile Dysfunction Induced by a High-Fat Diet

“…We suggest that the protective effect of ALDH2 is due to inhibition of JNK/AP-1 pathway. In the heart, both JNK and AP-1 are key regulators of myocardial remodeling [11,29]. In addition, hypertension-induced cardiac dysfunction is associated with increased AP-1 activity [5].…”

“…ALDH2 activation correlates strongly with cardioprotective effects in a number of model systems [8][9][10]. ALDH2 is activated by several pathways, including the c-Jun N-terminal kinase (JNK)/activated protein-1 (AP-1) pathway, which plays an important role in cardiac remodeling and cellular apoptosis [11,12]. JNK regulates the activity of numerous mitochondrial and nuclear proteins by phosphorylation [13].…”