Mixed Lineage Kinase-c-Jun N-Terminal Kinase Axis: A Potential Therapeutic Target in Cancer

Abstract

Mixed lineage kinases (MLKs) are members of the mitogen-activated protein kinase kinase kinase (MAP3K) family and are reported to activate MAP kinase pathways. There have been at least 9 members of the MLK family identified to date, although the physiological functions of all the family members are yet unknown. However, MLKs in general have been implicated in neurodegenerative diseases, including Parkinson and Alzheimer diseases. Recent reports suggest that some of the MLK members could play a role in cancer via modulating cell migration, invasion, cell cycle, and apoptosis. This review article will first describe the biology of MLK members and then discuss the current progress that relates to their functions in cancer.

Genetic and Genomic Characterization of 462 Melanoma Patient-Derived Xenografts, Tumor Biopsies, and Cell Lines

“…Pre-clinical modeling of response to therapies for NF1 mutated melanoma also will need to account for co-occurring mutations. The NF1 mutant cohort harboring co-mutations in MAPK3K5/9 is of particular interest as they are upstream activators of the Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase pathways (Rana et al, 2013). The current study provides the reagents to further functionally characterize this interesting rare subtype of melanoma.…”

p38MAPK activation mediates tumor necrosis factor-α-induced apoptosis in glioma cells

“…The mitogen-activated protein kinase (MAPK) cascade is essential in the transduction of signals from the extracellular space to the nucleus (2). Four signaling pathways of the MAPK family have been identified in eukaryotic cells as follows: (i) The extracellular signal-regulated protein kinase (ERK); (ii) c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK); (iii) ERK5/big MAP kinase (BMK1); and (iv) p38MAPK pathways (3). p38MAPK is a kinase induced by stress signals and can also be referred to as p38αMAPK (4).…”

Human Epidermal Growth Factor Receptor 2 (HER2) Impedes MLK3 Kinase Activity to Support Breast Cancer Cell Survival

“…In addition, we also reported recently that MLK3 kinase activity was down-regulated by IGF-1 and estrogen via activation of PI3K/AKT pathway (11). Specifically, the AKT activation, either by IGF-1 or estrogen directly, phosphorylates MLK3 on the Ser 674 site (13), and this phosphorylation suppresses the MLK3 kinase activity and prevents cancer cell death (13).…”

“…MLK3 is a member of a larger mixed lineage kinase (MLK) family, and the members are unique in the sense that their catalytic domains contain signature sequences of both serine/threonine and tyrosine kinases (11). Previous works by us and others have reported that MLK family members, including MLK3, activate c-Jun N-terminal kinase (JNK) (12).…”