title: Leucine Zipper-bearing Kinase promotes axon growth in mammalian central nervous system neurons.
abstract: Leucine Zipper-bearing Kinase (LZK/MAP3K13) is a member of the mixed lineage kinase family with high sequence identity to Dual Leucine Zipper Kinase (DLK/MAP3K12). While DLK is established as a key regulator of axonal responses to injury, the role of LZK in mammalian neurons is poorly understood. By gain- and loss-of-function analyses in neuronal cultures, we identify LZK as a novel positive regulator of axon growth. LZK signals specifically through MKK4 and JNKs among MAP2Ks and MAPKs respectively in neuronal cells, with JNK activity positively regulating LZK protein levels. Neuronal maturation or activity deprivation activates the LZK-MKK4-JNK pathway. LZK and DLK share commonalities in signaling, regulation, and effects on axon extension. Furthermore, LZK-dependent regulation of DLK protein expression and the lack of additive effects on axon growth upon co-manipulation suggest complex functional interaction and cross-regulation between these two kinases. Together, our data support the possibility for two structurally related MAP3Ks to work in concert to mediate axonal responses to external insult or injury in mammalian CNS neurons.
authors: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, 92093, USA.
authors: Meifan
authors: M
authors: Chen
authors: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, 92093, USA.
authors: Cédric G
authors: CG
authors: Geoffroy
authors: Renal Electrolyte and Hypertension Division, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors: Hetty N
authors: HN
authors: Wong
authors: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, 92093, USA.
authors: Oliver
authors: O
authors: Tress
authors: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, 92093, USA.
authors: Mallorie T
authors: MT
authors: Nguyen
authors: Renal Electrolyte and Hypertension Division, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors: Lawrence B
authors: LB
authors: Holzman
authors: Section of Neurobiology, Division of Biological Sciences, and Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, 92093, USA.
authors: Yishi
authors: Y
authors: Jin
authors: Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, California, 92093, USA.
authors: Binhai
authors: B
authors: Zheng
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000201:enzymology*; D015870:Gene Expression; D055786:Gene Knockout Techniques; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice
chemical_list: C000621586:Lzk protein, mouse; D020930:MAP Kinase Kinase Kinases