P120-Ras GTPase activating protein (RasGAP): A multi-interacting protein in downstream signaling

Pamonsinlapatham, Perayot; Hadj-Slimane, Réda; Lepelletier, Yves; Allain, Barbara; Toccafondi, Mirco; Garbay, Christiane; Raynaud, Françoise

doi:10.1016/j.biochi.2008.10.010

Cited by 107 publications

(101 citation statements)

References 96 publications

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“…Different domain arrangements in GAPs to create differential protein-protein and proteinlipid interactions are probably key factors determining the GTP/GDP ratio bound to H−, K−, and N-Ras. 14,[24][25][26][27][28][29][30] Cell-and animal-based studies examining GAP activity, interaction partners, and expression profiles have provided further insights into Ras inactivation in normal and transformed cells. Mammalian proteins capable of functioning as GAPs for H-, K-, and N-Ras represent a large and divergent protein family and include p120GAP, neurofibromin (NF1), the GAP1 family, including GAP1 IP4BP , Ca 2+ -promoted Ras inactivator (CAPRI), Ras GTPase activating-like protein RASAL, as well as the SynGAP family (DAB2IP, nGAP, SynGAP).…”

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

“…Mammalian proteins capable of functioning as GAPs for H-, K-, and N-Ras represent a large and divergent protein family and include p120GAP, neurofibromin (NF1), the GAP1 family, including GAP1 IP4BP , Ca 2+ -promoted Ras inactivator (CAPRI), Ras GTPase activating-like protein RASAL, as well as the SynGAP family (DAB2IP, nGAP, SynGAP). 14,[24][25][26][27][28][29][30] Some of those are expressed ubiquitously, while others show very restricted expression profiles, making it difficult to assign a member of the GAP family with Ras inactivation in a given cell/tissue. In addition, structural analysis indicated that NF1 and p120GAP bind Ras isoforms without any preference.…”

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

“…In support of this hypothesis, the different domain arrangements in GAPs point at different functions and interactions. [24][25][26][27][28][29][30] …”

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

“…As described in more detail below, the various protein domains and second messengers promoting membrane association of NF1, p120GAP, CAPRI, RASAL, GAP1 m , GAP1 IP4BP , and SynGAP probably reflect the need and adaptation to ensure efficient targeting of all Ras isoforms in any cellular location. All GAPs are characterized by a multiple domain structure, [24][25][26][27][28][29][30] and modules such as the src homology 2 (SH2), SH3, pleckstrin homology (PH), Ca 2+ -dependent phospholipid-binding/conserved region 2 (CALB/C2), and the Bruton tyrosine kinase Cys-rich (BTK) domain probably enable targeting of any Ras isoform by at least one GAP independent of Ras isoform microdomain localization. But little is yet known how protein-protein and protein-lipid interactions and calcium (Ca 2+ ) coordinate the targeting of the GAP family members to different Ras isoforms in various locations in different cells and tissues.…”

Section: Subcellular Localization Of Ras Signaling Complexesmentioning

confidence: 99%

“…In addition, the differential interaction of GAPs with growth factor receptors, protein kinase C (PKC), but also regulators of actin remodeling, such as RhoGAPs and Rac/Rho GTPases, and other yet unknown proteins provides further opportunity for signal complex specificity. 14,[24][25][26][27][28][29][30] To date, experimental evidence for GAP activity is almost exclusively associated with Ras inactivation at the plasma membrane. NF1 has been found at the plasma membrane and multiple intracellular localizations and could thus be involved in Ras inactivation in various endomembranes.…”

Section: Subcellular Localization Of Ras Signaling Complexesmentioning

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: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

“…In support of this hypothesis, the different domain arrangements in GAPs point at different functions and interactions. [24][25][26][27][28][29][30] …”

Section: Functional Differences Of Ras Isoforms and Differential Gap mentioning

confidence: 99%

Section: Subcellular Localization Of Ras Signaling Complexesmentioning

confidence: 99%

Section: Subcellular Localization Of Ras Signaling Complexesmentioning

confidence: 99%

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Differential Regulation of RasGAPs in Cancer

et al. 2011

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Prospects of Modulating Protein–Protein Interactions

Zhong

Oashi

et al. 2012

Protein‐Ligand Interactions

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Another face of RASA1: Report of familial germline variant in RASA1 with dysmorphic features

Hume,

Cossio,

Vargas

et al. 2024

American J of Med Genetics Pt A

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RASopathies encompass a diverse set of disorders affecting genes that encode proteins within the RAS‐MAPK pathway. RASA1 mutations are the cause of an autosomal dominant disorder called capillary malformation‐arteriovenous malformation type 1 (CM‐AVM1). Unlike other RASopathies, facial dysmorphism has not been described in these patients. We phenotypically delineated a large family of individuals with multifocal fast‐flow capillary malformations, severe lymphatic anomalies of perinatal onset, and dysmorphic features not previously described. Sequencing studies were performed on probands and related family members, confirming the segregation of dysmorphic features in affected members of a novel heterozygous variant in RASA1 (NM_002890.3:c.2366G>A, p.(Arg789Gln)). In this work, we broaden the phenotypic spectrum of CM‐AVM type 1 and propose a new RASA1 variant as likely pathogenic.

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P120-Ras GTPase activating protein (RasGAP): A multi-interacting protein in downstream signaling

Cited by 107 publications

References 96 publications

Differential Regulation of RasGAPs in Cancer

Differential Regulation of RasGAPs in Cancer

Prospects of Modulating Protein–Protein Interactions

Another face of RASA1: Report of familial germline variant in RASA1 with dysmorphic features

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