PLEKHG2 Promotes Heterotrimeric G Protein βγ-Stimulated Lymphocyte Migration via Rac and Cdc42 Activation and Actin Polymerization

Runne, Caitlin; Chen, Songhai

doi:10.1128/mcb.00879-13

Cited by 20 publications

(17 citation statements)

References 49 publications

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“…Swap70 44 ) or can directly bind Gβγ (Dbl 45 ), the synergistic activation by PIP 3 and Gβγ is unique to the P-Rex family. Several other Rac-GEFs can be activated by Gβγ in vivo, including PLEKHG2 46 and DOCK180/Elmo1, 47 but as yet without evidence for direct activation in vitro. The most promising example for direct Gβγ-dependent activation of GEFs other than P-Rex is for DOCK/Elmo complexes in Dictyostelium, where direct Gβγ binding to ElmoE was suggested by FRET, 48 although direct Gβγ-dependent activation of DOCK/Elmo remains to be confirmed with recombinant proteins.…”

Section: Regulation Of Activitymentioning

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: Regulation Of Activitymentioning

confidence: 99%

Regulation and function of P-Rex family Rac-GEFs

Welch

2015

Small GTPases

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“…Cdc42 is a vital factor in cell phagocytosis, which is an actin-dependent process essential to the host defense mechanism (9). Cdc42 plays a role in actin polymerization (10)(11)(12) and can regulate gene transcription in various signaling pathways, such as the NF-B, NOD1, c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase (MAPK) pathways (7,13). Alternatively, several RNA virus species, including human immunodeficiency virus type 1 (HIV-1), respiratory syncytial virus (RSV), and Ebola virus (EBOV), have developed a diverse repertoire of mechanisms to hijack cellular actin-regulating signaling pathways as part of their cell entry processes.…”

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confidence: 99%

Interaction of the Small GTPase Cdc42 with Arginine Kinase Restricts White Spot Syndrome Virus in Shrimp

Jiang

Wei

et al. 2017

J Virol

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Many types of small GTPases are widely expressed in eukaryotes and have different functions. As a crucial member of the Rho GTPase family, Cdc42 serves a number of functions, such as regulating cell growth, migration, and cell movement. Several RNA viruses employ Cdc42-hijacking tactics in their target cell entry processes. However, the function of Cdc42 in shrimp antiviral immunity is not clear. In this study, we identified a Cdc42 protein in the kuruma shrimp (Marsupenaeus japonicus) and named it MjCdc42. MjCdc42 was upregulated in shrimp challenged by white spot syndrome virus (WSSV). The knockdown of MjCdc42 and injection of Cdc42 inhibitors increased the proliferation of WSSV. Further experiments determined that MjCdc42 interacted with an arginine kinase (MjAK). By analyzing the binding activity and enzyme activity of MjAK and its mutant, ΔMjAK, we found that MjAK could enhance the replication of WSSV in shrimp. MjAK interacted with the envelope protein VP26 of WSSV. An inhibitor of AK activity, quercetin, could impair the function of MjAK in WSSV replication. Further study demonstrated that the binding of MjCdc42 and MjAK depends on Cys 271 of MjAK and suppresses the WSSV replication-promoting effect of MjAK. By interacting with the active site of MjAK and suppressing its enzyme activity, MjCdc42 inhibits WSSV replication in shrimp. Our results demonstrate a new function of Cdc42 in the cellular defense against viral infection in addition to the regulation of actin and phagocytosis, which has been reported in previous studies. IMPORTANCEThe interaction of Cdc42 with arginine kinase plays a crucial role in the host defense against WSSV infection. This study identifies a new mechanism of Cdc42 in innate immunity and enriches the knowledge of the antiviral innate immunity of invertebrates.

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“…activity of PLEKHG2. Recently, we and other researchers suggested that the C terminus of PLEKHG2 might interact with the N terminus of PLEKHG2, and this interaction could impose a constraint on the normal DH domain function by masking the access of the Rho GTPase (9,15). It has been hypothesized that, when PLEKHG2 is activated, the interaction between the C and N termini is canceled, and the DH domain functions as a guanine nucleotide exchange factor for the Rho protein.…”

Section: The Interaction Of Plekhg2/flj00018 With Fhl1mentioning

confidence: 99%

Four-and-a-half LIM Domains 1 (FHL1) Protein Interacts with the Rho Guanine Nucleotide Exchange Factor PLEKHG2/FLJ00018 and Regulates Cell Morphogenesis

Sato

Kimura

Sugiyama

et al. 2016

Journal of Biological Chemistry

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PLEKHG2/FLJ00018 is a Gβγ-dependent guanine nucleotide exchange factor for the small GTPases Rac and Cdc42 and has been shown to mediate the signaling pathways leading to actin cytoskeleton reorganization. Here we showed that the zinc finger domain-containing protein four-and-a-half LIM domains 1 (FHL1) acts as a novel interaction partner of PLEKHG2 by the yeast two-hybrid system. Among the isoforms of FHL1 (i.e. FHL1A, FHL1B, and FHL1C), FHL1A and FHL1B interacted with PLEKHG2. We found that there was an FHL1-binding region at amino acids 58-150 of PLEKHG2. The overexpression of FHL1A but not FHL1B enhanced the PLEKHG2-induced serum response element-dependent gene transcription. The co-expression of FHL1A and Gβγ synergistically enhanced the PLEKHG2-induced serum response element-dependent gene transcription. Increased transcription activity was decreased by FHL1A knock-out with the CRISPR/Cas9 system. Compared with PLEKHG2-expressing cells, the number and length of finger-like protrusions were increased in PLEKHG2-, Gβγ-, and FHL1A-expressing cells. Our results provide evidence that FHL1A interacts with PLEKHG2 and regulates cell morphological change through the activity of PLEKHG2.

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PLEKHG2 Promotes Heterotrimeric G Protein βγ-Stimulated Lymphocyte Migration via Rac and Cdc42 Activation and Actin Polymerization

Cited by 20 publications

References 49 publications

Regulation and function of P-Rex family Rac-GEFs

Regulation and function of P-Rex family Rac-GEFs

Interaction of the Small GTPase Cdc42 with Arginine Kinase Restricts White Spot Syndrome Virus in Shrimp

Four-and-a-half LIM Domains 1 (FHL1) Protein Interacts with the Rho Guanine Nucleotide Exchange Factor PLEKHG2/FLJ00018 and Regulates Cell Morphogenesis

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