JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Abstract

SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity

“…Known functional associations of Jnk/Mapk signaling include roles in differentiation, apoptosis, and migration. It is believed that the diverse roles are due to the large number of Jnk interacting factors [58]. The suggestion from work in mouse is that migration defects is the major consequence of loss of Jnk signaling, since RET S697A mutant mice, which have impaired Mapk signaling (among other signaling defects), exhibit impaired cell migration without alterations in cell proliferation or survival [33].…”

Coxsackievirus B Tailors the Unfolded Protein Response to Favour Viral Amplification in Pancreatic β Cells

“…JNK has 2 main isoforms, JNK1 and JNK2 [44]. JNK1 is the main contributor to cytokine-induced β cell apoptosis [45].…”

High expression of ubiquitin-conjugating enzyme E2A predicts poor prognosis in hepatocellular carcinoma

“…Despite advances in the diagnosis (8) and treatment (9) of HCC, the prognosis of this disease remains poor (10). Therefore, further clarification of the mechanisms underlying its development is important (11,12).…”

“…Despite advances in the diagnosis (8) and treatment (9) of HCC, the prognosis of this disease remains poor (10). Therefore, further clarification of the mechanisms underlying its development is important (11,12).At present, the prognosis of HCC is predicted based on imaging findings and biomarkers. Various biomarkers, including α-fetoprotein (AFP) (13), des-γ-ca rboxy prothrombin (14) and α-l-fucosidase (15), have been identified over the past three decades.…”