PLEKHG2

Last updated
PLEKHG2
Identifiers
Aliases PLEKHG2 , ARHGEF42, CLG, LDAMD, pleckstrin homology and RhoGEF domain containing G2, CTB-60E11.4
External IDs OMIM: 611893; MGI: 2141874; HomoloGene: 16341; GeneCards: PLEKHG2; OMA:PLEKHG2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

64857

101497

Ensembl

ENSG00000090924

ENSMUSG00000037552

UniProt

Q9H7P9

Q6KAU7

RefSeq (mRNA)

NM_022835
NM_001351693
NM_001351694

NM_001083912
NM_001290542
NM_138752

RefSeq (protein)

NP_073746
NP_001338622
NP_001338623

NP_001077381
NP_001277471
NP_620091

Location (UCSC) Chr 19: 39.41 – 39.43 Mb Chr 7: 28.36 – 28.37 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Pleckstrin homology domain containing, family G member 2 (PLEKHG2) is a protein that in humans is encoded by the PLEKHG2 gene. It is sometimes written as ARHGEF42, FLJ00018.

Contents

The PLEKHG2 protein is a huge protein of about 1300 amino acids, 130 kDa and has a Dbl homology (DH) domain and a pleckstrin homology (PH) domain near the N terminus of its structure. The DH domain is a domain responsible for guanine nucleotide exchange activity that converts GDP on the Rho family Small GTPase (RhoGTPase) to GTP, and PLEKHG2 having this domain also acts as a Rho-specific guanine nucleotide exchange factor (RhoGEF).

Activation of RhoGTPase reconstitute the actin cytoskeleton and changes the cell morphology, so PLEKHG2 might be contributes to cell motility and neuronal network development of neurons via RhoGTPase and actin remodeling (see later).

Cloning

Recombinant BXH2 and AKXD inbred mice mutated by retroviral transduction are known to develop myeloid leukemia, B cell and T cell leukemia at high frequency. [5]

In 2002, Himmel et al., used this model of acute myelogenous leukemia and showed that a novel Dbl family guanine nucleotide exchange factor gene is contained downstream of the retroviral uptake site called Evi24. They named this gene Clg. Hemmel and colleagues cloned Clg and showed homology with PLEKHG2 contained in human chromosome 19 chromosome 19q13.1 region. From these observations they pointed out association with acute myeloid leukemia. [6]

Functions

In a paper published by Hemmel et al., in 2002, they showed that a construct containing a DH-PH domain of Clg promotes guanine nucleotide exchange of Cdc42 but does not promote guanine nucleotide exchange of Rac1 or RhoA. In addition, DH-PH domains or full-length Clg were introduced into NIH3T3 cells and transformation occurred.

Later, Ueda and his colleagues introduced the expression construct of full-length human PLEKHG2 into HEK 293 cells. In this cell the Gβγ subunit of the trimeric G protein were interacted with PLEKHG2 directly. Ueda and colleagues also showed that PLEKHG2 were activated by Gbg and PLEKHG2 activates Rac1, Cdc42 of RhoGTPase and contributes to cell morphological change. [7]

In 2013, Runne et al., showed that PLEKHG2 is elevated in several leukemia cell lines, including Jurkat T cells. In addition, they showed that GPCR signal-dependent activation of Rac and Cdc42 regulates the chemotaxis of lymphocytes via actin polymerization. From this observation PLEKHG2 was considered to an important regulator of cell motility. [8]

Furthermore, in recent years, it has become clear that PLEKHG2 undergoes regulation through modification such as phosphorylation and interaction with other proteins by various intracellular signals (see the section on interaction / protein modification). However, the function in vivo is still unclear.

In 2016, Edvardson et al., identified homozygosity for Arg204Trp mutation in the PLEKHG2 gene in the patients with dystonia or postnatal microcephaly. [9]

Interactions

PLEKHG2 is known to interacted with the following proteins.

・Gβγ [7]

・β-actin [10]

・Four and a Half LIM domain1 (FHL1) [11] [12]

・Gαs [13]

protein modification

It is known that PLEKHG2 undergoes modification such as phosphorylation by the following signals.

・SRC [14]

・EGFR [15]

Related Research Articles

<span class="mw-page-title-main">Guanine nucleotide exchange factor</span> Proteins which remove GDP from GTPases

Guanine nucleotide exchange factors (GEFs) are proteins or protein domains that activate monomeric GTPases by stimulating the release of guanosine diphosphate (GDP) to allow binding of guanosine triphosphate (GTP). A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity. Some GEFs can activate multiple GTPases while others are specific to a single GTPase.

The Rho family of GTPases is a family of small signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic kingdoms, including yeasts and some plants. Three members of the family have been studied in detail: Cdc42, Rac1, and RhoA. All G proteins are "molecular switches", and Rho proteins play a role in organelle development, cytoskeletal dynamics, cell movement, and other common cellular functions.

<span class="mw-page-title-main">CDC42</span> Protein-coding gene in the species Homo sapiens

Cell division control protein 42 homolog is a protein that in humans is encoded by the CDC42 gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.

<span class="mw-page-title-main">FGD1</span> Protein-coding gene in the species Homo sapiens

FYVE, RhoGEF and PH domain-containing protein 1 (FGD1) also known as faciogenital dysplasia 1 protein (FGDY), zinc finger FYVE domain-containing protein 3 (ZFYVE3), or Rho/Rac guanine nucleotide exchange factor FGD1 is a protein that in humans is encoded by the FGD1 gene that lies on the X chromosome. Orthologs of the FGD1 gene are found in dog, cow, mouse, rat, and zebrafish, and also budding yeast and C. elegans. It is a member of the FYVE, RhoGEF and PH domain containing family.

<span class="mw-page-title-main">Transforming protein RhoA</span> Protein and coding gene in humans

Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the RHOA gene. While the effects of RhoA activity are not all well known, it is primarily associated with cytoskeleton regulation, mostly actin stress fibers formation and actomyosin contractility. It acts upon several effectors. Among them, ROCK1 and DIAPH1 are the best described. RhoA, and the other Rho GTPases, are part of a larger family of related proteins known as the Ras superfamily, a family of proteins involved in the regulation and timing of cell division. RhoA is one of the oldest Rho GTPases, with homologues present in the genomes since 1.5 billion years. As a consequence, RhoA is somehow involved in many cellular processes which emerged throughout evolution. RhoA specifically is regarded as a prominent regulatory factor in other functions such as the regulation of cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.

<span class="mw-page-title-main">RhoGEF domain</span> Protein domain

RhoGEF domain describes two distinct structural domains with guanine nucleotide exchange factor (GEF) activity to regulate small GTPases in the Rho family. Rho small GTPases are inactive when bound to GDP but active when bound to GTP; RhoGEF domains in proteins are able to promote GDP release and GTP binding to activate specific Rho family members, including RhoA, Rac1 and Cdc42.

<span class="mw-page-title-main">ARHGEF7</span> Protein-coding gene in humans

Rho guanine nucleotide exchange factor 7 is a protein that in humans is encoded by the ARHGEF7 gene.

<span class="mw-page-title-main">ARHGEF6</span> Protein-coding gene in humans

Rho guanine nucleotide exchange factor 6 is a protein that, in humans, is encoded by the ARHGEF6 gene.

<span class="mw-page-title-main">ARHGEF11</span> Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 11 is a protein that in humans is encoded by the ARHGEF11 gene. This protein is also called RhoGEF11 or PDZ-RhoGEF.

<span class="mw-page-title-main">ARHGEF12</span> Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 12 is a protein that in humans is encoded by the ARHGEF12 gene. This protein is also called RhoGEF12 or Leukemia-associated Rho guanine nucleotide exchange factor (LARG).

<span class="mw-page-title-main">RhoG</span> Protein-coding gene in the species Homo sapiens

RhoG is a small monomeric GTP-binding protein, and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene RHOG.

<span class="mw-page-title-main">VAV3</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide exchange factor VAV3 is a protein that in humans is encoded by the VAV3 gene.

<span class="mw-page-title-main">MCF2L</span> Gene found in humans

Guanine nucleotide exchange factor DBS is a protein that in humans is encoded by the MCF2L gene.

Rac is a subfamily of the Rho family of GTPases, small signaling G proteins. Just as other G proteins, Rac acts as a molecular switch, remaining inactive while bound to guanosine diphosphate (GDP) and activated once guanine nucleotide exchange factors (GEFs) remove GDP, permitting guanosine triphosphate (GTP) to bind. When bound to GTP, Rac is activated. In its activated state, Rac participates in the regulation of cell movement, through its involvement in structural changes to the actin cytoskeleton. By changing the cytoskeletal dynamics within the cell, Rac-GTPases are able to facilitate the recruitment of neutrophils to the infected tissues, and to regulate degranulation of azurophil and integrin-dependent phagocytosis.

<span class="mw-page-title-main">Dedicator of cytokinesis protein 10</span> Protein found in humans

Dedicator of cytokinesis protein 10 (Dock10), also known as Zizimin3, is a large protein involved in intracellular signalling networks that in humans is encoded by the DOCK10 gene. It is a member of the DOCK-D subfamily of the DOCK family of guanine nucleotide exchange factors, which function as activators of small G-proteins.

<span class="mw-page-title-main">GNA12</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide-binding protein subunit alpha-12 is a protein that in humans is encoded by the GNA12 gene.

<span class="mw-page-title-main">ARHGEF4</span> Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 4 is a protein that in humans is encoded by the ARHGEF4 gene.

<span class="mw-page-title-main">Dedicator of cytokinesis protein 6</span> Protein found in humans

Dedicator of cytokinesis protein 6 (Dock6), also known as Zir1 is a large protein encoded in the human by the DOCK6 gene, involved in intracellular signalling networks. It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors which function as activators of small G-proteins.

<span class="mw-page-title-main">Dedicator of cytokinesis protein 11</span> Protein-coding gene in humans

Dedicator of cytokinesis protein 11 (Dock11), also known as Zizimin2, is a large protein encoded in the human by the DOCK11 gene, involved in intracellular signalling networks. It is a member of the DOCK-D subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock11 activates the small G protein Cdc42.

<span class="mw-page-title-main">ARHGAP31</span> Protein-coding gene in the species Homo sapiens

The Rho GTPase activating protein 31 is encoded in humans by the ARHGAP31 gene. It is a Cdc42/Rac1 GTPase regulator.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000090924 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000037552 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Li, J.; Shen, H.; Himmel, K. L.; Dupuy, A. J.; Largaespada, D. A.; Nakamura, T.; Shaughnessy, J. D.; Jenkins, N. A.; Copeland, N. G. (November 1999). "Leukaemia disease genes: large-scale cloning and pathway predictions". Nature Genetics. 23 (3): 348–353. doi:10.1038/15531. ISSN   1061-4036. PMID   10610183. S2CID   20338802.
  6. ↑ Himmel, Karen L.; Bi, Feng; Shen, Haifa; Jenkins, Nancy A.; Copeland, Neal G.; Zheng, Yi; Largaespada, David A. (2002-04-19). "Activation of clg, a novel dbl family guanine nucleotide exchange factor gene, by proviral insertion at evi24, a common integration site in B cell and myeloid leukemias". The Journal of Biological Chemistry. 277 (16): 13463–13472. doi: 10.1074/jbc.M110981200 . ISSN   0021-9258. PMID   11839748.
  7. 1 2 Ueda, Hiroshi; Nagae, Rika; Kozawa, Mika; Morishita, Rika; Kimura, Shinji; Nagase, Takahiro; Ohara, Osamu; Yoshida, Satoshi; Asano, Tomiko (2008-01-25). "Heterotrimeric G Protein βγ Subunits Stimulate FLJ00018, a Guanine Nucleotide Exchange Factor for Rac1 and Cdc42". Journal of Biological Chemistry. 283 (4): 1946–1953. doi: 10.1074/jbc.m707037200 . ISSN   0021-9258. PMID   18045877.
  8. ↑ Runne, Caitlin; Chen, Songhai (2013-11-01). "PLEKHG2 Promotes Heterotrimeric G Protein βγ-Stimulated Lymphocyte Migration via Rac and Cdc42 Activation and Actin Polymerization". Molecular and Cellular Biology. 33 (21): 4294–4307. doi:10.1128/mcb.00879-13. ISSN   0270-7306. PMC   3811901 . PMID   24001768.
  9. ↑ Edvardson, Simon; Wang, Haibo; Dor, Talya; Atawneh, Osamah; Yaacov, Barak; Gartner, Jutta; Cinnamon, Yuval; Chen, Songhai; Elpeleg, Orly (January 2016). "Microcephaly-dystonia due to mutated PLEKHG2 with impaired actin polymerization". Neurogenetics. 17 (1): 25–30. doi:10.1007/s10048-015-0464-y. ISSN   1364-6753. PMID   26573021. S2CID   18626551.
  10. ↑ Sato, Katsuya; Handa, Hiroaki; Kimura, Masashi; Okano, Yukio; Nagaoka, Hitoshi; Nagase, Takahiro; Sugiyama, Tsuyoshi; Kitade, Yukio; Ueda, Hiroshi (2013). "Identification of a Rho family specific guanine nucleotide exchange factor, FLJ00018, as a novel actin-binding protein". Cellular Signalling. 25 (1): 41–49. doi:10.1016/j.cellsig.2012.09.015. PMID   23000341.
  11. ↑ Sato, Katsuya; Kimura, Masashi; Sugiyama, Kazue; Nishikawa, Masashi; Okano, Yukio; Nagaoka, Hitoshi; Nagase, Takahiro; Kitade, Yukio; Ueda, Hiroshi (2016-11-25). "Four-and-a-half LIM Domains 1 (FHL1) Protein Interacts with the Rho Guanine Nucleotide Exchange Factor PLEKHG2/FLJ00018 and Regulates Cell Morphogenesis". Journal of Biological Chemistry. 291 (48): 25227–25238. doi: 10.1074/jbc.m116.759571 . ISSN   0021-9258. PMC   5122788 . PMID   27765816.
  12. ↑ Nishikawa, Masashi; Sato, Katsuya; Nakano, Shun; Yamakawa, Hisashi; Nagase, Takahiro; Ueda, Hiroshi (2017-05-10). "Specific activation of PLEKHG2-induced serum response element-dependent gene transcription by four-and-a-half LIM domains (FHL) 1, but not FHL2 or FHL3". Small GTPases. 10 (5): 361–366. doi:10.1080/21541248.2017.1327838. ISSN   2154-1256. PMC   6748362 . PMID   28489964.
  13. ↑ Sugiyama, Kazue; Tago, Kenji; Matsushita, Sayumi; Nishikawa, Masashi; Sato, Katsuya; Muto, Yoshinori; Nagase, Takahiro; Ueda, Hiroshi (April 2017). "Heterotrimeric G protein Gαs subunit attenuates PLEKHG2, a Rho family-specific guanine nucleotide exchange factor, by direct interaction". Cellular Signalling. 32: 115–123. doi:10.1016/j.cellsig.2017.01.022. ISSN   1873-3913. PMID   28108261.
  14. ↑ Sato, Katsuya; Suzuki, Takahiro; Yamaguchi, Yoshihiro; Kitade, Yukio; Nagase, Takahiro; Ueda, Hiroshi (April 2014). "PLEKHG2/FLJ00018, a Rho family-specific guanine nucleotide exchange factor, is tyrosine phosphorylated via the EphB2/cSrc signaling pathway". Cellular Signalling. 26 (4): 691–696. doi:10.1016/j.cellsig.2013.12.006. ISSN   1873-3913. PMID   24378532.
  15. ↑ Sato, Katsuya; Sugiyama, Tsuyoshi; Nagase, Takahiro; Kitade, Yukio; Ueda, Hiroshi (2014-04-04). "Threonine 680 phosphorylation of FLJ00018/PLEKHG2, a Rho family-specific guanine nucleotide exchange factor, by epidermal growth factor receptor signaling regulates cell morphology of Neuro-2a cells". The Journal of Biological Chemistry. 289 (14): 10045–10056. doi: 10.1074/jbc.M113.521880 . ISSN   1083-351X. PMC   3974976 . PMID   24554703.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.