Insights into the biological functions of Dock family guanine nucleotide exchange factors

Laurin, Mélanie; Côté, Jean‐François

doi:10.1101/gad.236349.113

Cited by 139 publications

(184 citation statements)

References 96 publications

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“…One example is the knockout of Ga 13 receptors in endothelial cells in mice, which causes a decrease in tumor growth and normalization of tumor vasculature. Ga 13 activates RhoA to induce transcription of VEGFR2 via NFkB. 143 Local invasion is an early step in the metastatic process by which cells need to detach from the primary tumor and migrate through the surrounding tissue.…”

Section: Rho Gtpases In Cancermentioning

confidence: 99%

“…The DHR-2 domain interacts with the nucleotide-free form of Rho GTPases and forms an intermediate in the catalytic reaction for exchange of GDP to GTP. 8,13 GTPase-activating factors (GAPs) are proteins that inactivate Rho GTPases by promoting the hydrolysis of GTP: they provide an essential catalytic group that accelerates the intrinsic GTPase activity of the GTPases. The human genome encodes around 80 RhoGAPs.…”

Section: Regulation Of Typical Rho Gtpases By Gefs Gaps and Gdismentioning

confidence: 99%

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Rho GTPases: Regulation and roles in cancer cell biology

Haga

Ridley²

2016

Small GTPases

417

390

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Rho GTPases are well known for their roles in regulating cell migration, and also contribute to a variety of other cellular responses. They are subdivided into 2 groups: typical and atypical. The typical Rho family members, including RhoA, Rac1 and Cdc42, cycle between an active GTP-bound and inactive GDP-bound conformation, and are regulated by GEFs, GAPs and GDIs, whereas atypical Rho family members have amino acid substitutions that alter their ability to interact with GTP/GDP and hence are regulated by different mechanisms. Both typical and atypical Rho GTPases contribute to cancer progression. In a few cancers, RhoA or Rac1 are mutated, but in most cancers expression levels and/or activity of Rho GTPases is altered. Rho GTPase signaling could therefore be therapeutically targeted in cancer treatment.

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Section: Rho Gtpases In Cancermentioning

confidence: 99%

Section: Regulation Of Typical Rho Gtpases By Gefs Gaps and Gdismentioning

confidence: 99%

Rho GTPases: Regulation and roles in cancer cell biology

Haga

Ridley²

2016

Small GTPases

417

390

View full text Add to dashboard Cite

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“…and Pleckstrin homology (PH) sequences (Gadea and Blangy 2014;Laurin and Côté 2014). Functionally, the DH domain catalyzes GEF activity, while the PH domain allows for interactions with other proteins to control subcellular localization (Rossman et al 2005;Cook et al 2014).…”

mentioning

confidence: 99%

Fine-Tuning of the Actin Cytoskeleton and Cell Adhesion During Drosophila Development by the Unconventional Guanine Nucleotide Exchange Factors Myoblast City and Sponge

2015

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The evolutionarily conserved Dock proteins function as unconventional guanine nucleotide exchange factors (GEFs). Upon binding to engulfment and cell motility (ELMO) proteins, Dock-ELMO complexes activate the Rho family of small GTPases to mediate a diverse array of biological processes, including cell motility, apoptotic cell clearance, and axon guidance. Overlapping expression patterns and functional redundancy among the 11 vertebrate Dock family members, which are subdivided into four families (Dock A, B, C, and D), complicate genetic analysis. In both vertebrate and invertebrate systems, the actin dynamics regulator, Rac, is the target GTPase of the Dock-A subfamily. However, it remains unclear whether Rac or Rap1 are the in vivo downstream GTPases of the Dock-B subfamily. Drosophila melanogaster is an excellent genetic model organism for understanding Dock protein function as its genome encodes one ortholog per subfamily: Myoblast city (Mbc; Dock A) and Sponge (Spg; Dock B). Here we show that the roles of Spg and Mbc are not redundant in the Drosophila somatic muscle or the dorsal vessel. Moreover, we confirm the in vivo role of Mbc upstream of Rac and provide evidence that Spg functions in concert with Rap1, possibly to regulate aspects of cell adhesion. Together these data show that Mbc and Spg can have different downstream GTPase targets. Our findings predict that the ability to regulate downstream GTPases is dependent on cellular context and allows for the fine-tuning of actin cytoskeletal or cell adhesion events in biological processes that undergo cell morphogenesis.

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“…Elmo proteins have no apparent enzymatic activity (4) and have been found to act as scaffolds for Dock (dedicator of cytokinesis) guanine nucleotide exchange factors (2). In addition, Elmo proteins have been found to interact with a panel of proteins, including BAI1-3 (5, 6), G␣ i2 (7), RhoG (8) and G␤␥ (9).…”

mentioning

confidence: 99%

“…Elmo proteins are characterized by the presence of a Ras GTPasebinding domain, a region that is present only in Elmo proteins and ElmoD protein (known as the ELMO domain), a pleckstrin homology (PH) 3 domain, and a proline-rich region (1,2). In addition, two regions in Elmo proteins were shown to mediate a closed and inactive conformation state, the Elmo-inhibitory domain and the Elmo autoregulation domain (3).…”

mentioning

confidence: 99%

Elmo2 Is a Regulator of Insulin-dependent Glut4 Membrane Translocation

Sun

Côté

2016

Journal of Biological Chemistry

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Elmo2, a member of the Elmo protein family, has been implicated in the regulation of Rac1 and Akt activation. Recently, we found that Elmo2 specifically interacts with ClipR-59. Because Akt and Rac1 have been implicated in insulin dependent Glut4 membrane translocation, we hypothesize here that Elmo2 may play a role in insulin-dependent Glut4 membrane translocation. Accordingly, we found that overexpression of Elmo2 enhanced, whereas its knockdown suppressed, insulin-dependent Glut4 membrane translocation in both 3T3-L1 adipocytes and L6 skeletal muscle cells. We also examined whether Elmo2 contributes to the insulin-mediated activation of Rac1 and Akt. We found that Elmo2 is required for insulin-induced Rac1 GTP loading, but not AKT activation, in L6 cells induced by insulin. Instead, Elmo2 is required to promote the insulin-induced membrane association of Akt. Together, our studies demonstrate that Elmo2 is a new regulator of insulin-dependent Glut4 membrane translocation through modulating Rac1 activity and Akt membrane compartmentalization.

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Insights into the biological functions of Dock family guanine nucleotide exchange factors

Cited by 139 publications

References 96 publications

Rho GTPases: Regulation and roles in cancer cell biology

Rho GTPases: Regulation and roles in cancer cell biology

Fine-Tuning of the Actin Cytoskeleton and Cell Adhesion During Drosophila Development by the Unconventional Guanine Nucleotide Exchange Factors Myoblast City and Sponge

Elmo2 Is a Regulator of Insulin-dependent Glut4 Membrane Translocation

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