Regulation of the actin cytoskeleton by the Ndel1-Tara complex is critical for cell migration

Abstract

Nuclear distribution element-like 1 (Ndel1) plays pivotal roles in diverse biological processes and is implicated in the pathogenesis of multiple neurodevelopmental disorders. Ndel1 function by regulating microtubules and intermediate filaments; however, its functional link with the actin cytoskeleton is largely unknown. Here, we show that Ndel1 interacts with TRIO-associated repeat on actin (Tara), an actin-bundling protein, to regulate cell movement. In vitro wound healing and Boyden chamber assays revealed that Ndel1- or Tara-deficient cells were defective in cell migration. Moreover, Tara overexpression induced the accumulation of Ndel1 at the cell periphery and resulted in prominent co-localization with F-actin. This redistribution of Ndel1 was abolished by deletion of the Ndel1-interacting domain of Tara, suggesting that the altered peripheral localization of Ndel1 requires a physical interaction with Tara. Furthermore, co-expression of Ndel1 and Tara in SH-SY5Y cells caused a synergistic increase in F-actin levels and filopodia formation, suggesting that Tara facilitates cell movement by sequestering Ndel1 at peripheral structures to regulate actin remodeling. Thus, we demonstrated that Ndel1 interacts with Tara to regulate cell movement. These findings reveal a novel role of the Ndel1-Tara complex in actin reorganization during cell movement.

An unpredicted aggregation-critical region of the actin-polymerizing protein TRIOBP-1/Tara, determined by elucidation of its domain structure

“…The central region is responsible for the assembly of TRIOBP-1 oligomers, forming an oligomeric state comparable with that previously described for the fulllength protein (18) and containing the aggregation-critical region. CC4 corresponds to the region of TRIOBP-1 recently identified to be required for interaction with NDEL1 and subsequent effects on cell migration (11) and also contains a known phosphorylation site of importance for mitotic progression (10). The central domain is also involved in neurite outgrowth, with its expression in isolation leading to a reduction in neurite number, possibly as a result of the truncation mutant having a dominant negative effect.…”

“…It is also involved in chromosome segregation during mitosis (10) as well as in cell migration. The latter occurs through its interaction with nuclear distribution element-like 1 (NDEL1) (11), a protein of significant importance in neurodevelopment that has been implicated in schizophrenia (12). Small, but statistically significant, increases in TRIOBP transcript expression have also been detected in post-mortem brain tissue of schizophrenia patients from two independent samples (13).…”

Characterizing how glycerol monolaurate (GML) affects human T cell signaling and function

“…Moreover, microtubules work in close concert with actin filaments in the cytoskeletal regulation of T cell activation [192]. Furthermore, the microtubule regulatory protein Ndel1 in conjunction with the actin bundling protein Tara synergistically induces filopodia structures, suggesting that microtubule function also plays a role in filopodia formation [193].…”

Sequential phosphorylation of NDEL1 by the DYRK2-GSK3β complex is critical for neuronal morphogenesis

“…NDEL1 directly binds to Trio-associated repeat on actin (TARA, also known as TRIOBP isoform 1) (Hong et al, 2016), a short isoform of Trio-binding protein (TRIOBP) generated by alternative splicing (Riazuddin et al, 2006; Seipel et al, 2001). TARA associates with filamentous actin (F-actin) and has functions in cell mitosis and cell migration (Hong et al, 2016; Seipel et al, 2001; Zhu et al, 2012).…”