LMTK1, a Novel Modulator of Endosomal Trafficking in Neurons.

Shin-Ichi Hisanaga,Anni Huo,Ran Wei,Mineko Tomomura

doi:10.3389/fnmol.2020.00112

Shin-Ichi Hisanaga, Anni Huo + Show 2 more

Open Access

https://doi.org/10.3389/fnmol.2020.00112

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Abstract

Neurons extend long processes known as axons and dendrites, through which they communicate with each other. The neuronal circuits formed by the axons and dendrites are the structural basis of higher brain functions. The formation and maintenance of these processes are essential for physiological brain activities. Membrane components, both lipids, and proteins, that are required for process formation are supplied by vesicle transport. Intracellular membrane trafficking is regulated by a family of Rab small GTPases. A group of Rabs regulating endosomal trafficking has been studied mainly in nonpolarized culture cell lines, and little is known about their regulation in polarized neurons with long processes. As shown in our recent study, lemur tail (former tyrosine) kinase 1 (LMTK1), an as yet uncharacterized Ser/Thr kinase associated with Rab11-positive recycling endosomes, modulates the formation of axons, dendrites, and spines in cultured primary neurons. LMTK1 knockdown or knockout (KO) or the expression of a kinase-negative mutant stimulates the transport of endosomal vesicles in neurons, leading to the overgrowth of axons, dendrites, and spines. More recently, we found that LMTK1 regulates TBC1D9B Rab11 GAP and proposed the Cdk5/p35-LMTK1-TBC1D9B-Rab11 pathway as a signaling cascade that regulates endosomal trafficking. Here, we summarize the biochemical, cell biological, and physiological properties of LMTK1.

Highlights

Neurons are highly polarized cells with two types of processes called the axon and dendrite
At least two major isoforms of LMTK1 are expressed in the mouse brain, LMTK1A and LMTK1B, which differ in the presence or absence of the N-terminal transmembrane sequences (Figure 1; Tomomura et al, 2007; Wei et al, 2020)
The D206V kinase negative (KN) mutant of LMTK1A is distributed throughout the cytoplasm (Takano et al, 2010). Both upstream and downstream proteins of LMTK1A are associated with endosomal membranes through different types of lipid modifications: cyclin-dependent kinase 5 (Cdk5) binds to membranes via the N-terminal myristoylation of its activator protein p35, LMTK1 is palmitoylated at the N-terminal region of transmembrane sequences and Rab11 is modified by geranylgeranylation (Figure 2B)

Summary

Introduction

Neurons are highly polarized cells with two types of processes called the axon and dendrite. As shown in our recent study, LMTK1 regulates axon outgrowth, dendrite arborization, and spine formation through Rab11dependent vesicle transport. At least two major isoforms of LMTK1 are expressed in the mouse brain, LMTK1A and LMTK1B, which differ in the presence or absence of the N-terminal transmembrane sequences (Figure 1; Tomomura et al, 2007; Wei et al, 2020).

Results

Conclusion