Ras and Rab Interactor 3: From Cellular Mechanisms to Human Diseases.

Ruinan Shen,Caitlin J Murphy,Mingzheng Hu,Jianqing Ding,Chengbiao Wu,Xiaowen Xu

doi:10.3389/fcell.2022.824961

Abstract

Ras and Rab interactor 3 (RIN3) functions as a Guanine nucleotide Exchange Factor (GEF) for some members of the Rab family of small GTPase. By promoting the activation of Rab5, RIN3 plays an important role in regulating endocytosis and endocytic trafficking. In addition, RIN3 activates Ras, another small GTPase, that controls multiple signaling pathways to regulate cellular function. Increasing evidence suggests that dysregulation of RIN3 activity may contribute to the pathogenesis of several disease conditions ranging from Paget’s Disease of the Bone (PDB), Alzheimer’s Disease (AD), Chronic Obstructive Pulmonary Disease (COPD) and to obesity. Recent genome-wide association studies (GWAS) identified variants in the RIN3 gene to be linked with these disease conditions. Interestingly, some variants appear to be missense mutations in the functional domains of the RIN3 protein while most variants are located in the noncoding regions of the RIN3 gene, potentially altering its gene expression. However, neither the protein structure of RIN3 nor its exact function(s) (except for its GEF activity) has been fully defined. Furthermore, how the polymorphisms/variants contribute to disease pathogenesis remain to be understood. Herein, we examine, and review published studies in an attempt to provide a better understanding of the physiological function of RIN3; More importantly, we construct a framework linking the polymorphisms/variants of RIN3 to altered cell signaling and endocytic traffic, and to potential disease mechanism(s).

Highlights

Specialty section: This article was submitted to Membrane Traffic, a section of the journal Frontiers in Cell and Developmental
Recent evidence has suggested that dysfunction of Rab interactor 3 (RIN3) is associated with several human diseases such as Paget’s disease of bone, Alzheimer’s disease, chronic pulmonary obstructive disease and obesity
All disease associated-missense mutations are located in the functional domains and could alter the function of RIN3 protein

Summary

Introduction

Specialty section: This article was submitted to Membrane Traffic, a section of the journal Frontiers in Cell and Developmental. RIN3 activates Ras, another small GTPase, that controls multiple signaling pathways to regulate cellular function. It was since suggested that any proteins that contained the same modularity and biochemical characteristic of the Vps9 domain may function as a GEF to activate Rab5 (Hama et al, 1999).

Results

Conclusion