Morphoregulatory functions of the RNA-binding motif protein 3 in cell spreading, polarity and migration

J Pilotte,P W Vanderklish,W Kiosses,E Dupont-Versteegden,S W Chan,H P Makarenkova

doi:10.1038/s41598-018-25668-2

J Pilotte, P W Vanderklish + Show 4 more

Open Access

https://doi.org/10.1038/s41598-018-25668-2

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Abstract

RNA-binding proteins are emerging as key regulators of transitions in cell morphology. The RNA-binding motif protein 3 (RBM3) is a cold-inducible RNA-binding protein with broadly relevant roles in cellular protection, and putative functions in cancer and development. Several findings suggest that RBM3 has morphoregulatory functions germane to its roles in these contexts. For example, RBM3 helps maintain the morphological integrity of cell protrusions during cell stress and disease. Moreover, it is highly expressed in migrating neurons of the developing brain and in cancer invadopodia, suggesting roles in migration. We here show that RBM3 regulates cell polarity, spreading and migration. RBM3 was present in spreading initiation centers, filopodia and blebs that formed during cell spreading in cell lines and primary myoblasts. Reducing RBM3 triggered exaggerated spreading, increased RhoA expression, and a loss of polarity that was rescued by Rho kinase inhibition and overexpression of CRMP2. High RBM3 expression enhanced the motility of cells migrating by a mesenchymal mode involving extension of long protrusions, whereas RBM3 knockdown slowed migration, greatly reducing the ability of cells to extend protrusions and impairing multiple processes that require directional migration. These data establish novel functions of RBM3 of potential significance to tissue repair, metastasis and development.

Highlights

The RNA-binding motif protein 3 (RBM3), a member of small family of cold-inducible RNA-binding proteins[1,2,3,4], regulates several aspects of mRNA metabolism and has pleiotropic functions in cell stress, development, and oncogenesis
We observed that RNAbinding motif protein 3 (RBM3) is present in multiple types of cell protrusions that form in a variety of cell lines and primary myoblasts, and that perturbation of RBM3 expression results in dramatic changes in cell polarity and spreading involving RhoA-Rho associated protein kinase (ROCK) signaling and the collapsin response mediator protein 2 (CRMP2)
Insofar as our prior work showed that RBM3 stimulates translation[5], the detection of RBM3 in spreading initiation centers (SICs) raised the possibility that it is a regulator of cell spreading

Summary

Introduction

The RNA-binding motif protein 3 (RBM3), a member of small family of cold-inducible RNA-binding proteins[1,2,3,4], regulates several aspects of mRNA metabolism and has pleiotropic functions in cell stress, development, and oncogenesis. Their functions at these loci can be multifold, including the regulation of mRNA localization and translation events that support cell adhesion, spreading, migration, and the guidance of extensions[31,32,33,41], and protein-protein interactions that regulate cytoskeletal dynamics[42] In light of such data, the presence of RBM3 in SICs and invasive filopodia suggests that it has morphoregulatory functions in cell shape and migration, which may be important to its stress response functions and putative involvement in development and cancer. These effects are discussed in terms of their potential relevance to cell protection and the processes of tissue repair, development, and metastatic processes involving migration mode flexibility

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