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Annu Rev Cell Dev Biol. 2019 Oct 6;35:501-521. doi: 10.1146/annurev-cellbio-100617-062644.

Multitasking: Dual Leucine Zipper-Bearing Kinases in Neuronal Development and Stress Management.

Jin Y1,2, Zheng B2,3.

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Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA; email:
Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA; email:
VA San Diego Healthcare System, San Diego, California 92161, USA.


The dual leucine zipper-bearing kinase (DLK) and leucine zipper-bearing kinase (LZK) are evolutionarily conserved MAPKKKs of the mixed-lineage kinase family. Acting upstream of stress-responsive JNK and p38 MAP kinases, DLK and LZK have emerged as central players in neuronal responses to a variety of acute and traumatic injuries. Recent studies also implicate their function in astrocytes, microglia, and other nonneuronal cells, reflecting their expanding roles in the multicellular response to injury and in disease. Of particular note is the potential link of these kinases to neurodegenerative diseases and cancer. It is thus critical to understand the physiological contexts under which these kinases are activated, as well as the signal transduction mechanisms that mediate specific functional outcomes. In this review we first provide a historical overview of the biochemical and functional dissection of these kinases. We then discuss recent findings on regulating their activity to enhance cellular protection following injury and in disease, focusing on but not limited to the nervous system.


Alzheimer disease models; DLK; DLK-1; HSV infection; JNK; LZK; MAP3K; Wallenda; adipogenesis; astrocytes; axon degeneration; axon regeneration; cytoskeleton; insulin β-cells; neuronal death; neuronal development; p38

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