P-Rex2, a Rac-guanine nucleotide exchange factor, is expressed selectively in ribbon synaptic terminals of the mouse retina

Sherry, David M.; Blackburn, Bradley A

doi:10.1186/1471-2202-14-70

Cited by 3 publications

(3 citation statements)

References 62 publications

(112 reference statements)

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“…5 ). Finally, a recent report suggested that P-Rex2 may also be expressed in mouse retinal neurons, 69 but this requires confirmation through knockdown or P-Rex2 −/− controls. For a detailed recent review on the role P-Rex1 and P-Rex2 in neuronal synaptic plasticity and behavior, see reference number.…”

Section: Physiological Functionmentioning

confidence: 99%

Regulation and function of P-Rex family Rac-GEFs

Welch

2015

Small GTPases

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The P-Rex family are Dbl-type guanine-nucleotide exchange factors for Rac family small G proteins. They are distinguished from other Rac-GEFs through their synergistic mode of activation by the lipid second messenger phosphatidyl inositol (3,4,5) trisphosphate and the Gbg subunits of heterotrimeric G proteins, thus acting as coincidence detectors for phosphoinositide 3-kinase and G protein coupled receptor signaling. Work in geneticallymodified mice has shown that P-Rex1 has physiological importance in the inflammatory response and the migration of melanoblasts during development, whereas P-Rex2 controls the dendrite morphology of cerebellar Purkinje neurons as well as glucose homeostasis in liver and adipose tissue. Deregulation of P-Rex1 and P-Rex2 expression occurs in many types of cancer, and P-Rex2 is frequently mutated in melanoma. Both GEFs promote tumor growth or metastasis. This review critically evaluates the P-Rex literature and tools available and highlights exciting recent developments and open questions.Rac family small G proteins (Rac1, Rac2, Rac3 and RhoG; a branch of the Rho family) control a myriad of essential cell responses, including adhesion, migration, reactive oxygen species formation and gene expression.1-3 They can be activated by 2 types of guanine-nucleotide exchange factors (GEFs), Dbl or DOCK, which are characterized by the structure of their catalytic domains. Rac-GEFs promote the release of GDP from Rac, allowing excess free cellular GTP to bind, and thus induce the active conformation of Rac which is able to engage downstream targets and stimulate cell responses [4][5][6] (Fig. 1).The P-Rex family are Dbl-type Rac-GEFs. The founding member, PIP 3 -dependent Rac exchanger 1, P-Rex1 (PREX1), was discovered during a search for factors that activate Rac when stimulated by the lipid second messenger phosphatidyl inositol (3,4,5) trisphosphate (PIP 3 ) which is generated by class I phosphoinositide 3-kinase (PI3K).7 P-Rex2 (PREX2) and P-Rex2b were discovered on the basis of their sequence homology with PRex1.8,9 P-Rex family proteins differ from other Dbl-type RacGEFs such as Vav, Tiam or Trio 4-6 in their domain structure and mechanisms of regulation. They have a number of physiological functions that are described in section "Physiological Function", an emerging role in metabolic disease that is discussed in section "Insulin Resistance and Type 2 Diabetes", and important roles in cancer progression that are described in section "Cancer". Genes and ProteinsThe coding sequence of the 2 P-Rex genes is 49% identical and conserved throughout vertebrates but absent from invertebrates.8 In humans, the P-Rex1 gene (PREX1; NM_020820) is located in chromosome 20 (20q13.13), near a region associated with type 2 diabetes, and the P-Rex2 gene (PREX2; NM_024870) on chromosome 8 (8q13.2), in a region linked to aggressive cancers and metastasis. PREX1 encodes the protein P-Rex1 (185 kDa, 1659 amino acids (aa); NP_065871), and PREX2 encodes 2 proteins, full-length P-Rex2 (also known as P-Rex2a; 183 k...

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Section: Physiological Functionmentioning

confidence: 99%

Regulation and function of P-Rex family Rac-GEFs

Welch

2015

Small GTPases

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“… 33 P-Rex2, GEF that specifically activates Rac small GTPases, is expressed by neurons in the peripheral and central nervous systems. 25 The present study was applied to determine the role of P-Rex2 in the development of the BCP. Our data have showed that P-Rex2 was upregulated in the spinal dorsal horn of the BCP mice.…”

Section: Discussionmentioning

confidence: 99%

“… 24 P-Rex2 is required for spine and synapse development and it has been shown that a decrease in P-Rex2 expression results in reduced spine density. 25 However, the overall link among P-Rex2 and AMPAR in BCP has not been reported.…”

Section: Introductionmentioning

confidence: 99%

P-Rex2 mediation of synaptic plasticity contributes to bone cancer pain

Huang²,

Li³

et al. 2022

Mol Pain

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Bone cancer pain (BCP) seriously affects the quality of life, however, due to its complex mechanism the clinical treatment was unsatisfactory. Recent studies have showed several Rac-specific guanine nucleotide exchange factor (GEF) that affect development and structure of neuronal processes play a vital role in the regulation of chronic pain. P-Rex2 is one of GEFs that regulate spine density, and the present study was performed to examine the effect of P-Rex2 on the development of BCP. Tumor cells implantation induced the mechanical hyperalgesia, which was accompanied by an increase in spinal protein P-Rex2, phosphorylated Rac1 (p-Rac1) and phosphorylated GluR1 (p-GluR1), and number of spines. Intrathecal injection a P-Rex2-targeting RNAi lentivirus relieved BCP and reduced the expression of P-Rex2, p-Rac1, p-GluR1and number of spines in the BCP mice. Meanwhile, P-Rex2 knockdown reversed BCP-enhanced AMPA receptor (AMPAR)-induced current in dorsal horn neurons. In summary, this study suggested that P-Rex2 regulated GluR1-containing AMPAR trafficking and spine morphology via Rac1/pGluR1 pathway is a fundamental pathogenesis of BCP. Our findings provide a better understanding of the function of P-Rex2 as a possible therapeutic target for relieving BCP.

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The guanine nucleotide exchange factor Vav3 regulates differentiation of progenitor cells in the developing mouse retina

et al. 2014

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The seven main cell types in the mammalian retina arise from multipotent retinal progenitor cells, a process that is tightly regulated by intrinsic and extrinsic signals. However, the molecular mechanisms that control proliferation, differentiation and cell-fate decisions of retinal progenitor cells are not fully understood yet. Here, we report that the guanine nucleotide exchange factor Vav3, a regulator of Rho-GTPases, is involved in retinal development. We demonstrate that Vav3 is expressed in the mouse retina during the embryonic period. In order to study the role of Vav3 in the developing retina, we generate Vav3-deficient mice. The loss of Vav3 results in an accelerated differentiation of retinal ganglion cells and cone photoreceptors during early and late embryonic development. We provide evidence that more retinal progenitor cells express the late progenitor marker Sox9 in Vav3-deficient mice than in wild-types. This premature differentiation is compensated during the postnatal period and late-born cell types such as bipolar cells and Müller glia display normal numbers. Taken together, our data imply that Vav3 is a regulator of retinal progenitor cell differentiation, thus highlighting a novel role for guanine nucleotide exchange factors in retinogenesis.

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P-Rex2, a Rac-guanine nucleotide exchange factor, is expressed selectively in ribbon synaptic terminals of the mouse retina

Cited by 3 publications

References 62 publications

Regulation and function of P-Rex family Rac-GEFs

Regulation and function of P-Rex family Rac-GEFs

P-Rex2 mediation of synaptic plasticity contributes to bone cancer pain

The guanine nucleotide exchange factor Vav3 regulates differentiation of progenitor cells in the developing mouse retina

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