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

Differential Regulation of RasGAPs in Cancer

“…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).…”

“…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.…”

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

“…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.…”

“…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.…”