Biology:PLEKHG2
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.
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.[1]
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.[2]
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.[3]
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.[4]
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.[5]
Interactions
PLEKHG2 is known to interacted with the following proteins.
・Gβγ[3]
・β-actin[6]
・Four and a Half LIM domain1 (FHL1)[7][8]
・Gαs[9]
protein modification
It is known that PLEKHG2 undergoes modification such as phosphorylation by the following signals.
・SRC[10]
・EGFR[11]
References
- ↑ Li, J.; Shen, H.; Himmel, K. L.; Dupuy, A. J.; Largaespada, D. A.; Nakamura, T.; Shaughnessy, J. D.; Jenkins, N. A. et al. (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.
- ↑ 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.
- ↑ 3.0 3.1 Ueda, Hiroshi; Nagae, Rika; Kozawa, Mika; Morishita, Rika; Kimura, Shinji; Nagase, Takahiro; Ohara, Osamu; Yoshida, Satoshi et al. (2008-01-25). "Heterotrimeric G Protein βγ Subunits Stimulate FLJ00018, a Guanine Nucleotide Exchange Factor for Rac1 and Cdc42" (in en). Journal of Biological Chemistry 283 (4): 1946–1953. doi:10.1074/jbc.m707037200. ISSN 0021-9258. PMID 18045877.
- ↑ Runne, Caitlin; Chen, Songhai (2013-11-01). "PLEKHG2 Promotes Heterotrimeric G Protein βγ-Stimulated Lymphocyte Migration via Rac and Cdc42 Activation and Actin Polymerization" (in en). Molecular and Cellular Biology 33 (21): 4294–4307. doi:10.1128/mcb.00879-13. ISSN 0270-7306. PMID 24001768.
- ↑ Edvardson, Simon; Wang, Haibo; Dor, Talya; Atawneh, Osamah; Yaacov, Barak; Gartner, Jutta; Cinnamon, Yuval; Chen, Songhai et al. (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.
- ↑ Sato, Katsuya; Handa, Hiroaki; Kimura, Masashi; Okano, Yukio; Nagaoka, Hitoshi; Nagase, Takahiro; Sugiyama, Tsuyoshi; Kitade, Yukio et al. (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.
- ↑ Sato, Katsuya; Kimura, Masashi; Sugiyama, Kazue; Nishikawa, Masashi; Okano, Yukio; Nagaoka, Hitoshi; Nagase, Takahiro; Kitade, Yukio et al. (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" (in en). Journal of Biological Chemistry 291 (48): 25227–25238. doi:10.1074/jbc.m116.759571. ISSN 0021-9258. PMID 27765816.
- ↑ 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. PMID 28489964.
- ↑ 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.
- ↑ 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.
- ↑ 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. PMID 24554703.
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