GAP1 Family Members Constitute Bifunctional Ras and Rap GTPase-activating Proteins

Kupzig, Sabine; Deaconescu, Delia; Bouyoucef, Dalila; Walker, Simon; Liu, Qing; Polte, Christian L.; Daumke, Oliver; Ishizaki, Toshimasa; Lockyer, Peter J.; Wittinghofer, Alfred; Cullen, Peter J.

doi:10.1074/jbc.m512802200

Cited by 73 publications

(116 citation statements)

References 46 publications

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“…Unlike Ras, Rap1 does not possess a glutamine at position 61, and RapGAPs do not employ a catalytic arginine residue (arginine finger) but provide an asparagine (asparagine thumb) to stimulate GTP hydrolysis. [12][13][14][15] Interestingly, the RasGAP domain of GAP1 IP4BP is sufficient to drive the hydrolysis of Rap1-GTP, 13 and recent studies suggest that the GAP domain of GAP1 IP4BP and RASAL can undergo conformational changes that enable them to interact with either Ras or Rap1. 15 Hence, both Ras and Rap1 GTPases might compete for GAP1 IP4BP and RASAL recruitment in cells, and the local concentration of Ras and Rap1 in any microenvironment might determine the biological activity of these GAPs.…”

Section: Gap1 M and Gap1 Ib4bpmentioning

confidence: 99%

“…[9][10][11] Interestingly, several members of the GAP1 family of RasGAPs display dual specificity to stimulate GTP hydrolysis of Ras as well as Rap1. 8,[12][13][14][15] While the requirement for dual GTPase activity of GAPs awaits further confirmation in physiological settings, one can envisage that GAPs simultaneously regulating Ras and other small GTPases could integrate multiple signal transduction pathways.…”

Section: Monographsmentioning

confidence: 99%

“…117 However, the ability of GAP1 IB4BP to function as a Rap1 GTPase-activating protein indicates that depending on the cellular microenvironment, GAP1 GAPs might target Rap1 as well as Ras GTPases. [12][13][14][15] Indeed, all GAP1 family members except GAP1 m and even Syn-GAP can stimulate Rap1-GTP hydrolysis. [12][13][14][15]118 At first, these unexpected findings appeared difficult to interprete, as GAPs specific for Ras and Rap1 act differently.…”

Section: Gap1 M and Gap1 Ib4bpmentioning

confidence: 99%

“…[12][13][14][15] Indeed, all GAP1 family members except GAP1 m and even Syn-GAP can stimulate Rap1-GTP hydrolysis. [12][13][14][15]118 At first, these unexpected findings appeared difficult to interprete, as GAPs specific for Ras and Rap1 act differently. Unlike Ras, Rap1 does not possess a glutamine at position 61, and RapGAPs do not employ a catalytic arginine residue (arginine finger) but provide an asparagine (asparagine thumb) to stimulate GTP hydrolysis.…”

Section: Gap1 M and Gap1 Ib4bpmentioning

confidence: 99%

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Differential Regulation of RasGAPs in Cancer

et al. 2011

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Ever since their discovery as cellular counterparts of viral oncogenes more than 25 years ago, much progress has been made in understanding the complex networks of signal transduction pathways activated by oncogenic Ras mutations in human cancers. The activity of Ras is regulated by nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and much emphasis has been put into the biochemical and structural analysis of the Ras/GAP complex. The mechanisms by which GAPs catalyze Ras-GTP hydrolysis have been clarified and revealed that oncogenic Ras mutations confer resistance to GAPs and remain constitutively active. However, it is yet unclear how cells coordinate the large and divergent GAP protein family to promote Ras inactivation and ensure a certain biological response. Different domain arrangements in GAPs to create differential protein-protein and protein-lipid interactions are probably key factors determining the inactivation of the 3 Ras isoforms H-, K-, and N-Ras and their effector pathways. In recent years, in vitro as well as cell-and animal-based studies examining GAP activity, localization, interaction partners, and expression profiles have provided further insights into Ras inactivation and revealed characteristics of several GAPs to exert specific and distinct functions. This review aims to summarize knowledge on the cell biology of RasGAP proteins that potentially contributes to differential regulation of spatiotemporal Ras signaling.

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Section: Gap1 M and Gap1 Ib4bpmentioning

confidence: 99%

Section: Monographsmentioning

confidence: 99%

Section: Gap1 M and Gap1 Ib4bpmentioning

confidence: 99%

Section: Gap1 M and Gap1 Ib4bpmentioning

confidence: 99%

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Differential Regulation of RasGAPs in Cancer

et al. 2011

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“…RASA3, also called GAPIII or IP4BP (inositol 1,3,4,5-tetrakisphosphate, IP4, binding protein), is a member of the GAP1 family of Ras GTPase-activating proteins (GAPs) (6). Membrane localization is critical for GAP activity for all family members, which are highly conserved and share a common domain structure (7,8). C2A and C2B domains are involved in membrane binding and calcium-dependent activation of some GAPs.…”

mentioning

confidence: 99%

Critical function for the Ras-GTPase activating protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis

Blanc

Ciciotte

Gwynn

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Phenotype-driven approaches to gene discovery using inbred mice have been instrumental in identifying genetic determinants of inherited blood dyscrasias. The recessive mutant scat (severe combined anemia and thrombocytopenia) alternates between crisis and remission episodes, indicating an aberrant regulatory feedback mechanism common to erythrocyte and platelet formation. Here, we identify a missense mutation (G125V) in the scat Rasa3 gene, encoding a Ras GTPase activating protein (RasGAP), and elucidate the mechanism producing crisis episodes. The mutation causes mislocalization of RASA3 to the cytosol in scat red cells where it is inactive, leading to increased GTP-bound Ras. Erythropoiesis is severely blocked in scat crisis mice, and ∼94% succumb during the second crisis (∼30 d of age) from catastrophic hematopoietic failure in the spleen and bone marrow. Megakaryopoiesis is also defective during crisis. Notably, the scat phenotype is recapitulated in zebrafish when rasa3 is silenced. These results highlight a critical, conserved, and nonredundant role for RASA3 in vertebrate hematopoiesis.

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Dual‐Specificity R as/ R ap GTPase Activating Proteins

Sot

2018

Encyclopedia of Life Sciences

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The small GTP‐binding proteins Ras and Rap regulate important cellular events switching between an activated GTP‐bound form and an inactivated GDP‐bound state. Guanine exchange factors (GEFs) control the GDP to GTP‐bound cycle, while the conversion, through hydrolysis, of GTP to GDP is catalysed by GTPase‐activating proteins (GAPs). The GAPs complete Ras and Rap catalytic site for efficient GTP hydrolysis. Although Ras and Rap are highly homologous, they possess different residues in the catalytic site. In consequence, Ras and Rap GTPase‐activating proteins (RasGAPs and RapGAPs) are structurally unrelated and use different mechanisms. Surprisingly, there are several RasGAPs with dual Ras/Rap specificity: SynGAP; GAP1 family members GAP1 IP4BP , Rasal and Capri; and Plexins. This characteristic was an intriguing issue for years, but today structural and biochemical studies have enlightened the overall general mechanism of these dual GAPs. Key Concepts Small GTP‐binding proteins Rap and Ras control different cellular signalling switching between inactive GDP and active GTP‐bound states. Ras and Rap GTPase‐activating proteins (RasGAPs and RapGAPs) inactivate their downstream signalling catalysing the GTP hydrolysis, using RasGAP and RapGAP domains. RasGAPs–Ras‐GTP interaction positions Ras Gln61, situated in switch II loop, for nucleophilic attack, while the GAP contributes an Arg (arginine finger) to neutralise unfavourable negative charges of the reaction intermediate. Rap has a Thr in position 61, and RapGAPs catalyse GTP hydrolysis, contributing an Asn (Asn thumb) for nucleophilic attack. There are five RasGAPs with dual Rap/Ras specificity: SynGAP, Rasal, GAP1 IP4BP , Capri and Plexin. Dual GAPs need extra‐GAP domains to act as RapGAPs. Dual GAPs promote a specific orientation of Rap switch II, locating Gln63 as the catalytic residue. Plexin‐Rap X‐ray structure showed that residues of GAP domain and an extra‐GAP motif (juxtamembrane segment) are responsible for Gln63 correct orientation. SynGAP, Rasal, GAP1 IP4BP , Plexin and Capri do not share the same residues, and thus they still need to be found.

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GAP1 Family Members Constitute Bifunctional Ras and Rap GTPase-activating Proteins

Abstract: GAP1IP4BP is a member of the GAP1 family of Ras GTPase-activating proteins (

Cited by 73 publications

References 46 publications

Differential Regulation of RasGAPs in Cancer

Differential Regulation of RasGAPs in Cancer

Critical function for the Ras-GTPase activating protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis

Dual‐Specificity R as/ R ap GTPase Activating Proteins

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