Exploring the multifaceted role of RASGRP1 in disease: immune, neural, metabolic, and oncogenic perspectives

Abstract

RAS guanyl releasing protein 1 (RASGRP1) is a guanine nucleotide exchange factor (GEF) characterized by the presence of a RAS superfamily GEF domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, specifically activating RAS through the exchange of bound GDP for GTP. Activation of RAS by RASGRP1 has a wide range of downstream effects at the cellular level. Thus, it is not surprising that many diseases are associated with RASGRP1 disorders. Here, we present an overview of the structure and function of RASGRP1, its crucial role in the development, expression, and regulation of immune cells, and its involvement in various signaling pathways. This review comprehensively explores the relationship between RASGRP1 and various diseases, elucidates the underlying molecular mechanisms of RASGRP1 in each disease, and identifies potential therapeutic targets. This study provides novel insights into the role of RASGRP1 in insulin secretion and highlights its potential as a therapeutic target for diabetes. The limitations and challenges associated with studying RASGRP1 in disease are also discussed.

Keywords: RASGRP1; diabetes; disease; immune system; neurological disorders; oncogenesis.

Figure 1.

RASGRP1 mediate RAS activation on T lymphocytes. Activation of the TCR results in tyrosine phosphorylation of the ζ chain of the receptor by Src family kinases and the resulting phosphotyrosines serve to recruit ZAP-70, which in turn phosphorylates the scaffold protein LAT at multiple sites. Among the signaling molecules recruited to phosphorylated LAT is PLCγ, which acts on phosphatidylinositol-4,5-bisphosphate in the plasma membrane to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). Calcium liberated from internal stores by IP3 acts on the calcium- and DAG-sensitive Ras exchange factor RASGRP1 and causes it to translocate to the Golgi, where DAG levels are relatively high. RasGRP1 activates Golgi-associated RAS on this compartment. (Created with http://Biorender.com).

Figure 2.

RASGRP1-mediated signaling pathway. (a) RAS activation causes phosphorylation of Raf, MEK, and ERK, and promotes cell proliferation and differentiation. (b) RAS activation in cancer leads to tumor cell proliferation and angiogenesis and promotes the expression of PD-L1 on the surface of tumor cells. The increased combination of tumor cell PD-L1 and immune cell PD-1 further leads to increased apoptosis of immune cells. (c) RAS activation in T cells causes proliferation, differentiation, and immune response. (Created with http://Biorender.com).

Figure 3.

Immune system affected by RASGRP1 deficiency. (a) The absence of RASGRP1preferentially affected positive selection and resulted in decreased numbers of both CD4+ and CD8+ single-positive thymocytes. (b) RASGRP1 deficiency impairs the development of B1-a cell subpopulations leading to reduced secretion of IgM antibodies as well as IL-10 and GM-CSF. (c) IgE-mediated degranulation is impaired in mast cells of Rasgrp1^−/− mice. (d) NK cells exhibited impaired cytotoxicity and cytokine production. (Created with http://Biorender.com).

Figure 4.

Changes in RASGRP1 expression in disease. (Created with http://Biorender.com).