Regulation of Ras Exchange Factors and Cellular Localization of Ras Activation by Lipid Messengers in T Cells

Abstract

The Ras-MAPK signaling pathway is highly conserved throughout evolution and is activated downstream of a wide range of receptor stimuli. Ras guanine nucleotide exchange factors (RasGEFs) catalyze GTP loading of Ras and play a pivotal role in regulating receptor-ligand induced Ras activity. In T cells, three families of functionally important RasGEFs are expressed: RasGRF, RasGRP, and Son of Sevenless (SOS)-family GEFs. Early on it was recognized that Ras activation is critical for T cell development and that the RasGEFs play an important role herein. More recent work has revealed that nuances in Ras activation appear to significantly impact T cell development and selection. These nuances include distinct biochemical patterns of analog versus digital Ras activation, differences in cellular localization of Ras activation, and intricate interplays between the RasGEFs during distinct T cell developmental stages as revealed by various new mouse models. In many instances, the exact nature of these nuances in Ras activation or how these may result from fine-tuning of the RasGEFs is not understood. One large group of biomolecules critically involved in the control of RasGEFs functions are lipid second messengers. Multiple, yet distinct lipid products are generated following T cell receptor (TCR) stimulation and bind to different domains in the RasGRP and SOS RasGEFs to facilitate the activation of the membrane-anchored Ras GTPases. In this review we highlight how different lipid-based elements are generated by various enzymes downstream of the TCR and other receptors and how these dynamic and interrelated lipid products may fine-tune Ras activation by RasGEFs in developing T cells.

The Transmembrane Adaptor Protein SCIMP Facilitates Sustained Dectin-1 Signaling in Dendritic Cells

“…In addition, SCIMP also binds Grb2, which can then recruit Sos proteins, well characterized exchange factors for Ras and activators of the Ras/ERK pathway. Products of PLC␥2 also activate another family of Ras exchange factors, RasGRP proteins, which activate Ras downstream of TCR, BCR, and other immunoreceptors (35). Clearly, there are multiple options of how SCIMP can contribute to Dectin-1-dependent ERK activation.…”

Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics

“…This allosteric activation depends sensitively on the nucleotide state of Ras (7) and contributes an important aspect of SOS biology. Functionally, this is thought to enable SOS to operate as an analog-to-digital converter through a Ras-GTP positive-feedback loop operating at the membrane, such as during T cell activation (8, 9). However, the nucleotide specificity of allosteric activation of the catalytic site remains poorly understood.…”

Molecular mechanisms and functional implications of polarized actin remodeling at the T cell immunological synapse

“…This would make sense given that class IA PI3Ks, the downstream targets of Ras and the key mediators of F-actin ring formation, localize to plasma membrane microclusters[49]. In T cells, Ras activation is mediated by the combined activities of RasGRP1 and SOS[115]. Whereas SOS associates directly with the LAT-SLP76 complex, RasGRP1 is recruited into the TCR signaling cascade by interacting with DAG in the synaptic membrane (Fig.…”