The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders
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Protein & Cell
REVIEW The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders Kaifan Zhang1,2, Yan Wang1&
2
, Tianda Fan , Cheng Zeng
1,3
, Zhong Sheng Sun1,2,3,4&
1
Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China 3 CAS Center for Excellence in Biotic Interactions, University of Chinese Academy of Sciences, Beijing 100049, China 4 State Key Laboratory of Integrated Management of Pest Insects and Rodents, Chinese Academy of Sciences, Beijing 100101, China & Correspondence: [email protected] (Y. Wang), [email protected] (Z. S. Sun) Received July 2, 2020 Accepted November 19, 2020
ABSTRACT
INTRODUCTION
The serine/threonine p21-activated kinases (PAKs), as main effectors of the Rho GTPases Cdc42 and Rac, represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity. PAKs show wide expression in the brain, but they differ in specific cell types, brain regions, and developmental stages. PAKs play an essential and differential role in controlling neural cytoskeletal remodeling and are related to the development and fate of neurons as well as the structural and functional plasticity of dendritic spines. PAK-mediated actin signaling and interacting functional networks represent a common pathway frequently affected in multiple neurodevelopmental and neurodegenerative disorders. Considering specific small-molecule agonists and inhibitors for PAKs have been developed in cancer treatment, comprehensive knowledge about the role of PAKs in neural cytoskeletal remodeling will promote our understanding of the complex mechanisms underlying neurological diseases, which may also represent potential therapeutic targets of these diseases.
Most neurons receive information from other neurons via synapses mainly formed on the surface of dendritic spines. Thus, the morphological plasticity and density of dendritic spines are crucial for the physiological functions of neurons. Dendritic spines consist of a network of actin filaments, whose polymerization and depolymerization can govern spine function and regulate synaptic plasticity. Dysfunction of synaptic cytoskeletal remodeling is closely related to diverse brain disorders (Yan et al., 2016). As the initially identified and main downstream effectors of the Rho family small GTPases Cdc42 and Rac1, PAKs (p21-activated kinases) represent a family of serine/threonine kinases that can connect cytoskeletal dynamics, mechanical forces, and neuron morphology (Daniels and Bokoch, 1999; Nobes and Hall, 1999). It is widely recognized that PAKs play a potent and diversified role in controlling the morphology, motility, and fate of neurons to maintain the normal function of dendritic spines (Manser et al., 1994; Jaffer and Chernoff, 2002; Rane and Minden, 2014). To date, six PAKs have been identified in mammals. Based on their structural differences and sequence homologies, PAKs are cla
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