The Role of Ras Guanine Nucleotide Releasing Protein 4 in FcϵRI-mediated Signaling, Mast Cell Function, and T Cell Development

Zhu, Minghua; Fuller, Deirdre M.; Zhang, Weiguo

doi:10.1074/jbc.m111.320580

Cited by 24 publications

(37 citation statements)

References 22 publications

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“…The lack of a difference between RasGRP1 KO and RasGRP1/3 DKO mice contrasts the finding of the Zhang group where RasGRP4-defient mice showed no impairment in β-selection, but the combined loss of RasGRP1 and 4 showed a more profound phenotype than RasGRP1 deficiency alone. This suggests that RasGRP4 could compensate somewhat for the loss of RasGRP1 [24]. The difference observed between RasGRP1/3 DKO and RasGRP1/4 DKO is likely due to relatively higher expression of RasGRP4 than RasGRP3 in DN3 thymocytes as reported by the Immunological Genome Project [24], [34].…”

Section: Discussionmentioning

confidence: 68%

“…Recent reports published by Zhu et al and Kortum et al showed that RasGRP1- and RasGRP1/4- deficient mice showed impaired development beyond DN3, suggesting impaired β-selection [24], [25]. However, the involvement of RasGRP family members in the hallmark events of β-selection was not explored in detail.…”

Section: Resultsmentioning

confidence: 99%

“…In a recent report by the Zhang group, RasGRP1 knock out (KO) mice were found to display a partial block in β-selection that was augmented by simultaneous elimination of RasGRP4. RasGRP4 KO mice did not display any impairment in β-selection [24]. Furthermore, a report from Kortum et al showed that RasGRP1 KO thymi showed increased ratios of DN/DP and DN3/DN4 compared to wildtype thymi, implying defects in β-selection [25].…”

Section: Introductionmentioning

confidence: 95%

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RasGRP1, but Not RasGRP3, Is Required for Efficient Thymic β-Selection and ERK Activation Downstream of CXCR4

et al. 2013

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T cell development is a highly dynamic process that is driven by interactions between developing thymocytes and the thymic microenvironment. Upon entering the thymus, the earliest thymic progenitors, called CD4−CD8− ‘double negative’ (DN) thymocytes, pass through a checkpoint termed “β-selection” before maturing into CD4+CD8+ ‘double positive’ (DP) thymocytes. β-selection is an important developmental checkpoint during thymopoiesis where developing DN thymocytes that successfully express the pre-T cell receptor (TCR) undergo extensive proliferation and differentiation towards the DP stage. Signals transduced through the pre-TCR, chemokine receptor CXCR4 and Notch are thought to drive β-selection. Additionally, it has long been known that ERK is activated during β-selection; however the pathways regulating ERK activation remain unknown. Here, we performed a detailed analysis of the β-selection events in mice lacking RasGRP1, RasGRP3 and RasGRP1 and 3. We report that RasGRP1 KO and RasGRP1/3 DKO deficient thymi show a partial developmental block at the early DN3 stage of development. Furthermore, DN3 thymocytes from RasGRP1 and RasGRP1/3 double knock-out thymi show significantly reduced proliferation, despite expression of the TCRβ chain. As a result of impaired β-selection, the pool of TCRβ+ DN4 is significantly diminished, resulting in inefficient DN to DP development. Also, we report that RasGRP1 is required for ERK activation downstream of CXCR4 signaling, which we hypothesize represents a potential mechanism of RasGRP1 regulation of β-selection. Our results demonstrate that RasGRP1 is an important regulator of proliferation and differentiation at the β-selection checkpoint and functions downstream of CXCR4 to activate the Ras/MAPK pathway.

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Section: Discussionmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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RasGRP1, but Not RasGRP3, Is Required for Efficient Thymic β-Selection and ERK Activation Downstream of CXCR4

et al. 2013

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“…The RasGRP family consists of four RasGEFs, RasGRP1-4. Work from our laboratory and others has shown that RasGRP1-deficient mice exhibit impaired transition through the b-selection checkpoint (28,29). Furthermore, RasGRP1-deficient mice show a dramatic defect in thymocyte-positive selection and invariant NK T cell development (30)(31)(32).…”

mentioning

confidence: 99%

“…Furthermore, RasGRP1-deficient mice show a dramatic defect in thymocyte-positive selection and invariant NK T cell development (30)(31)(32). Aside from RasGRP1, only RasGRP4 has been shown to contribute to T cell development, specifically during the b-selection checkpoint (29). Roles for RasGRP2 or RasGRP3 have not been thoroughly examined in the context of T lymphopoiesis.…”

mentioning

confidence: 99%

RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors

Golec

Caviedes

Baldwin

2016

The Journal of Immunology

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T cell development is dependent on the migration of progenitor cells from the bone marrow to the thymus. Upon reaching the thymus, progenitors undergo a complex developmental program that requires inputs from various highly conserved signaling pathways including the Notch and Wnt pathways. To date, Ras signaling has not been implicated in the very earliest stages of T cell differentiation, but members of a family of Ras activators called RasGRPs have been shown to be involved at multiple stages of T cell development. We examined early T cell development in mice lacking RasGRP1, RasGRP3, and RasGRPs 1 and 3. We report that RasGRP1- and RasGRP3-deficient thymi show significantly reduced numbers of early thymic progenitors (ETPs) relative to wild type thymi. Furthermore, RasGRP1/3 double-deficient thymi show significant reductions in ETP numbers compared with either RasGRP1 or RasGRP3 single-deficient thymi, suggesting that both RasGRP1 and RasGRP3 regulate the generation of ETPs. In addition, competitive bone marrow chimera experiments reveal that RasGRP1/3 double-deficient progenitors intrinsically generate ETPs less efficiently than wild type progenitors. Finally, RasGRP1/3-deficient progenitors show impaired migration toward the CCR9 ligand, CCL25, suggesting that RasGRP1 and RasGRP3 may regulate progenitor entry into the thymus through a CCR9-dependent mechanism. These data demonstrate that, in addition to Notch and Wnt, the highly conserved Ras pathway is critical for the earliest stages of T cell development and further highlight the importance of Ras signaling during thymocyte maturation.

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RasGRP Ras guanine nucleotide exchange factors in cancer

2013

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Summary RasGRP proteins are activators of Ras and other related small GTPases by the virtue of functioning as guanine nucleotide exchange factors (GEFs). In vertebrates, four RasGRP family members have been described. RasGRP-1 through −4 share many structural domains but there are also subtle differences between each of the different family members. Whereas SOS RasGEFs are ubiquitously expressed, RasGRP proteins are expressed in distinct patterns, such as in different cells of the hematopoietic system and in the brain. Most studies have concentrated on the role of RasGRP proteins in the development and function of immune cell types because of the predominant RasGRP expression profiles in these cells and the immune phenotypes of mice deficient for Rasgrp genes. However, more recent studies demonstrate that RasGRPs also play an important role in tumorigenesis. Examples are skin- and hematological-cancers but also solid malignancies such as melanoma or prostate cancer. These novel studies bring up many new and unanswered questions related to the molecular mechanism of RasGRP-driven oncogenesis, such as new receptor systems that RasGRP appears to respond to as well as regulatory mechanism for RasGRP expression that appear to be perturbed in these cancers. Here we will review some of the known aspects of RasGRP biology in lymphocytes and will discuss the exciting new notion that RasGRP Ras exchange factors play a role in oncogenesis downstream of various growth factor receptors.

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The Role of Ras Guanine Nucleotide Releasing Protein 4 in FcϵRI-mediated Signaling, Mast Cell Function, and T Cell Development

Cited by 24 publications

References 22 publications

RasGRP1, but Not RasGRP3, Is Required for Efficient Thymic β-Selection and ERK Activation Downstream of CXCR4

RasGRP1, but Not RasGRP3, Is Required for Efficient Thymic β-Selection and ERK Activation Downstream of CXCR4

RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors

RasGRP Ras guanine nucleotide exchange factors in cancer

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