RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors

Thompson, Andrew; Bitsina, Christina; Gray, Janine L.; Delft, F. von; Brennan, P.E.

doi:10.1016/j.jbc.2021.100521

Cited by 15 publications

(14 citation statements)

References 137 publications

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“…Members of the dedicator of cytokinesis (Dock) family are noted for the catalytic Dock homology region 2 (DHR2) GEF domain and the DHR1 domain, located C-terminally to DHR2 and involved in membrane localisation (48). Dbl family GEFs are known to exhibit varied specificities to Rho GTPases, whereas the Dock family are thought to be restricted to Rac/Cdc42 regulation [reviewed in (49)(50)(51)]. Although, recent work has shown reduced RhoA activity due to downregulation of Dock1 in triple negative breast cancer epithelial cells (52).…”

Section: Rhogefs In Plateletsmentioning

confidence: 99%

Turning Platelets Off and On: Role of RhoGAPs and RhoGEFs in Platelet Activity

Comer

2022

Front. Cardiovasc. Med.

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Platelet cytoskeletal reorganisation is a critical component of platelet activation and thrombus formation in haemostasis. The Rho GTPases RhoA, Rac1 and Cdc42 are the primary drivers in the dynamic reorganisation process, leading to the development of filopodia and lamellipodia which dramatically increase platelet surface area upon activation. Rho GTPases cycle between their active (GTP-bound) and inactive (GDP-bound) states through tightly regulated processes, central to which are the guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs catalyse the dissociation of GDP by inducing changes in the nucleotide binding site, facilitating GTP binding and activating Rho GTPases. By contrast, while all GTPases possess intrinsic hydrolysing activity, this reaction is extremely slow. Therefore, GAPs catalyse the hydrolysis of GTP to GDP, reverting Rho GTPases to their inactive state. Our current knowledge of these proteins is constantly being updated but there is considerably less known about the functionality of Rho GTPase specific GAPs and GEFs in platelets. In the present review, we discuss GAP and GEF proteins for Rho GTPases identified in platelets, their regulation, biological function and present a case for their further study in platelets.

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Section: Rhogefs In Plateletsmentioning

confidence: 99%

Turning Platelets Off and On: Role of RhoGAPs and RhoGEFs in Platelet Activity

Comer

2022

Front. Cardiovasc. Med.

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“…GEFs activate small GTPases by stimulating GDP-GTP exchange, thus promoting their signaling-active states. Therefore, we tested whether the GEF activity of Dock7 was required to trigger mTORC1 signaling by creating a full-length Dock7 mutant construct that contains a mutation in the conserved, catalytic valine residue within the GEF domain that renders Dock proteins GEF-defective 44 . Interestingly, overexpression of the Dock7 GEF defective mutant (Dock7-GDM-V5) promoted S6K phosphorylation to a similar extent as wild-type Dock7, suggesting that Dock7 GEF activity is dispensable for the ability of Dock7 to activate mTORC1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

A multiprotein signaling complex sustains AKT and mTOR/S6K activity necessary for the survival of cancer cells undergoing stress

Teran

Zanotelli

Lin

et al. 2023

Preprint

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Cancer cells, both within a developing tumor and during metastatic spread, encounter many stresses that require adaptive mechanisms to survive and maintain malignant progression. Here we describe a signaling complex involving the small GTPase Cdc42 and Dock7, a Cdc42/Rac GEF and unique Cdc42-effector, that has a previously unappreciated role in regulating AKT, mTOR, and other mTOR signaling and regulatory partners including the TSC1/TCS2 complex and S6K during serum starvation. Dock7 is highly expressed in triple-negative breast cancers and is essential for the malignant properties in nutrient-deprived growth conditions of several cancer cell lines. We find that Dock7 interacts with phosphorylated AKT to maintain a low, but critical activation of a rapamycin-sensitive and Raptor-independent mTORC1-like activity required for survival during nutrient stress. Following the knock-out of Dock7 from cancer cells, interactions between AKT and the phosphatase PHLPP increased while phosphorylation of AKT at Ser473 decreased, suggesting Dock7 protects AKT from dephosphorylation. The DHR1 domain of Dock7, previously of unknown function, is responsible for maintaining AKT Ser473 phosphorylation during serum starvation through an interaction requiring its C2-like motif. Together, these findings indicate that Dock7 protects and maintains the phosphorylation of AKT to sustain a tonic mTOR/S6K activity in cancer cells necessary for their resistance to anoikis and to prevent them from undergoing apoptosis during stressful conditions.

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“…In this review, we mostly focus on the structure and mechanisms of human DOCK‐family proteins. Other DOCK proteins were recently reviewed in [ 18 , 28 ].…”

Section: Figmentioning

confidence: 99%

Structural biology of DOCK‐family guanine nucleotide exchange factors

2022

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Edited by Jacqueline Cherfils DOCK proteins are a family of multi-domain guanine nucleotide exchange factors (GEFs) that activate the RHO GTPases CDC42 and RAC1, thereby regulating several RHO GTPase-dependent cellular processes. DOCK proteins are characterized by the catalytic DHR2 domain (DOCK DHR2 ), and a phosphatidylinositol(3,4,5)P 3 -binding DHR1 domain (DOCK DHR1 ) that targets DOCK proteins to plasma membranes. DOCK-family GEFs are divided into four subfamilies (A to D) differing in their specificities for CDC42 and RAC1, and the composition of accessory signalling domains. Additionally, the DOCK-A and DOCK-B subfamilies are constitutively associated with ELMO proteins that auto-inhibit DOCK GEF activity. We review structural studies that have provided mechanistic insights into DOCK-protein functions. These studies revealed how a conserved nucleotide sensor in DOCK DHR2 catalyses nucleotide exchange, the basis for how different DOCK proteins activate specifically CDC42 and RAC1, and sometimes both, and how upstream regulators relieve the ELMO-mediated auto-inhibition. We conclude by presenting a model for full-length DOCK9 of the DOCK-D subfamily. The involvement of DOCK GEFs in a range of diseases highlights the importance of gaining structural insights into these proteins to better understand and specifically target them.

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RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors

Cited by 15 publications

References 137 publications

Turning Platelets Off and On: Role of RhoGAPs and RhoGEFs in Platelet Activity

Turning Platelets Off and On: Role of RhoGAPs and RhoGEFs in Platelet Activity

A multiprotein signaling complex sustains AKT and mTOR/S6K activity necessary for the survival of cancer cells undergoing stress

Structural biology of DOCK‐family guanine nucleotide exchange factors

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