A Ras-induced conformational switch in the Ras activator Son of sevenless

Freedman, Tanya S.; Sondermann, Holger; Friedland, Gregory D.; Kortemme, Tanja; Bar–Sagi, Dafna; Marqusee, Susan; Kuriyan, John

doi:10.1073/pnas.0608127103

Cited by 129 publications

(170 citation statements)

References 35 publications

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“…Structures of two other Cdc25 domains from Ras GEFs, SOS and RasGRF1, have been reported and share the same basic fold (Boriack-Sjodin et al, 1998;Freedman et al, 2006). The overall structure of our RalGPS1a Cdc25 domain exhibits high similarity with those of SOS and RasGRF1.…”

Section: Comparison With Other Known Cdc25 Structuresmentioning

confidence: 54%

“…An isolated SOS Cdc25 domain was unable to stimulate nucleotide exchange of Ras. However, an isolated RasGRF1 Cdc25 domain has comparable catalytic ability to the activated SOS (Freedman et al, 2006). Earlier studies attributed this variation in catalytic ability to conformational variations of the helical hairpin in the corresponding Cdc25 domains (Freedman et al, 2006).…”

Section: Conformation Of the Helical Hairpinmentioning

confidence: 95%

“…However, an isolated RasGRF1 Cdc25 domain has comparable catalytic ability to the activated SOS (Freedman et al, 2006). Earlier studies attributed this variation in catalytic ability to conformational variations of the helical hairpin in the corresponding Cdc25 domains (Freedman et al, 2006). The helical hairpin of the inactive SOS Cdc25 domain adopts an inward-rotated conformation which hinders binding of the Ras substrate.…”

Section: Conformation Of the Helical Hairpinmentioning

confidence: 98%

“…Evidence has shown that this PH domain directly interacts with certain components of the plasma membrane, such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 1,4,5-trisphosphate (PIP3), and is required for the membrane association of RalGPS1a and its biological activities in cells (Rameh et al, 1997;de Bruyn et al, 2000). The REM (Ras exchange motif) domain, normally located on the N-terminal side of the Cdc25 domain in the RalGDS family and other Ras GEFs, such as SOS, RasGRF1 (Freedman et al, 2006), and Epac2 , is absent in RalGPS proteins. The REM domain has been shown to stabilize the Cdc25 domain and to regulate its activity (Boriack-Sjodin et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…A positive feedback mechanism of SOS was later proposed based on the structure of a Ras-GTP complex bound to a cleft between the cdc25 and REM domains of SOS, which is distal to the active site of SOS (Margarit et al, 2003). Subsequently, the crystal structures of Rap GEF Epac2 (Rehmann et al, 2006) and Ras GEF RasGRF1 (Freedman et al, 2006) revealed a similar fold in their Cdc25 domains to that of SOS. Nevertheless, with the exception of the SOS-Ras complex, there have been no reported structures of other Ras GEF family proteins in complex with their substrates, and thus the structural basis for the substrate specificity of the GEF proteins remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Structural study of the Cdc25 domain from Ral-specific guanine-nucleotide exchange factor RalGPS1a

Peng

Guan

et al. 2011

Protein Cell

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The guanine-nucleotide exchange factor (GEF) RalGPS1a activates small GTPase Ral proteins such as RalA and RalB by stimulating the exchange of Ral bound GDP to GTP, thus regulating various downstream cellular processes. RalGPS1a is composed of an Nterminal Cdc25-like catalytic domain, followed by a PXXP motif and a C-terminal pleckstrin homology (PH) domain. The Cdc25 domain of RalGPS1a, which shares about 30% sequence identity with other Cdc25-domain proteins, is thought to be directly engaged in binding and activating the substrate Ral protein. Here we report the crystal structure of the Cdc25 domain of RalGPS1a. The bowl shaped structure is homologous to the Cdc25 domains of SOS and RasGRF1. The most remarkable difference between these three Cdc25 domains lies in their active sites, referred to as the helical hairpin region. Consistent with previous enzymological studies, the helical hairpin of RalGPS1a adopts a conformation favorable for substrate binding. A modeled RalGPS1a-RalA complex structure reveals an extensive binding surface similar to that of the SOS-Ras complex. However, analysis of the electrostatic surface potential suggests an interaction mode between the RalGPS1a active site helical hairpin and the switch 1 region of substrate RalA distinct from that of the SOS-Ras complex.

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Section: Comparison With Other Known Cdc25 Structuresmentioning

confidence: 54%

Section: Conformation Of the Helical Hairpinmentioning

confidence: 95%

Section: Conformation Of the Helical Hairpinmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Structural study of the Cdc25 domain from Ral-specific guanine-nucleotide exchange factor RalGPS1a

Peng

Guan

et al. 2011

Protein Cell

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SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma

Theard,

Linke,

Sealover

et al. 2024

Molecular Oncology

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Son of sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic receptor tyrosine kinase (RTK)‐dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR tyrosine kinase inhibitor (EGFR‐TKI) osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion (SOS2KO) sensitized EGFR‐mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit phosphatidylinositol 3‐kinase (PI3K)/AKT pathway activation, oncogenic transformation, and survival. Bypassing RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR‐TKIs; SOS2KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET‐driven bypass model, SOS2KO inhibited hepatocyte growth factor (HGF)‐stimulated PI3K signaling to block HGF‐driven osimertinib resistance. Using a long‐term in situ resistance assay, most osimertinib‐resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT‐dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2KO cultures that became osimertinib resistant primarily underwent non‐RTK‐dependent epithelial–mesenchymal transition (EMT). Since bypassing RTK reactivation and/or tertiary EGFR mutations represent most osimertinib‐resistant cancers, these data suggest that targeting proximal RTK signaling, here exemplified by SOS2 deletion, has the potential to delay the development osimertinib resistance and enhance overall clinical responses for patients with EGFR‐mutated LUAD.

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PPDPF Promotes the Development of Mutant KRAS‐Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1

Zheng

et al. 2022

Advanced Science

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The guanine nucleotide exchange factor (GEF) SOS1 catalyzes the exchange of GDP for GTP on RAS. However, regulation of the GEF activity remains elusive. Here, the authors report that PPDPF functions as an important regulator of SOS1. The expression of PPDPF is significantly increased in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and recurrence of PDAC patients. Overexpression of PPDPF promotes PDAC cell growth in vitro and in vivo, while PPDPF knockout exerts opposite effects. Pancreatic‐specific deletion of PPDPF profoundly inhibits tumor development in KRASG12D‐driven genetic mouse models of PDAC. PPDPF can bind GTP and transfer GTP to SOS1. Mutations of the GTP‐binding sites severely impair the tumor‐promoting effect of PPDPF. Consistently, mutations of the critical amino acids mediating SOS1–PPDPF interaction significantly impair the GEF activity of SOS1. Therefore, this study demonstrates a novel model of KRAS activation via PPDPF‐SOS1 axis, and provides a promising therapeutic target for PDAC.

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A Ras-induced conformational switch in the Ras activator Son of sevenless

Cited by 129 publications

References 35 publications

Structural study of the Cdc25 domain from Ral-specific guanine-nucleotide exchange factor RalGPS1a

Structural study of the Cdc25 domain from Ral-specific guanine-nucleotide exchange factor RalGPS1a

SOS2 modulates the threshold of EGFR signaling to regulate osimertinib efficacy and resistance in lung adenocarcinoma

PPDPF Promotes the Development of Mutant KRAS‐Driven Pancreatic Ductal Adenocarcinoma by Regulating the GEF Activity of SOS1

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