**Sanda Win, Tin Aung Than and Neil Kaplowitz \***

Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; swin@usc.edu (S.W.); tthan@usc.edu (T.A.T.) **\*** Correspondence: kaplowit@usc.edu

Received: 25 October 2018; Accepted: 17 November 2018; Published: 20 November 2018

**Abstract:** c-Jun-N-terminal kinase (JNK) activity plays a critical role in modulating cell death, which depends on the level and duration of JNK activation. The kinase cascade from MAPkinase kinase kinase (MAP3K) to MAPkinase kinase (MAP2K) to MAPKinase (MAPK) can be regulated by a number of direct and indirect post-transcriptional modifications, including acetylation, ubiquitination, phosphorylation, and their reversals. Recently, a JNK-mitochondrial SH3-domain binding protein 5 (SH3BP5/SAB)-ROS activation loop has been elucidated, which is required to sustain JNK activity. Importantly, the level of SAB expression in the outer membrane of mitochondria is a major determinant of the set-point for sustained JNK activation. SAB is a docking protein and substrate for JNK, leading to an intramitochondrial signal transduction pathway, which impairs electron transport and promotes reactive oxygen species (ROS) release to sustain the MAPK cascade.

**Keywords:** reactive oxygen species; PTPN6; SRC; DOK4; p38; MKK4; MKK7; p53; DUSP1; SIRT2
