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Fetal Growth Factors*
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
Philip A. Gruppuso, Thomas R. Curran, Roderick I. Bahner
Other purported substrates for the EGF receptor tyrosine kinase have been reported. GAP (GTPase activating protein), a protein which activates the GTPase activity of ras, is phosphorylated on tyrosine in response to EGF.59 Tyrosine phosphorylation of GAP is associated with its translocation to the membrane, possibly to form a complex with ras. Activation of ras, a protooncogene involved in stimulation of cell proliferation, may be relevant to the mitogenic effects of EGF.59
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Hydrolysis of GTP occurs through three main mechanisms: (1) intrinsic GTPase activity of the α-subunit, (2) specific GTPase-activating proteins, named regulators of G protein signaling (RGSs), and (3) some effectors. The α-subunits have two domains, a ras-like GTPase domain which includes the sites for guanine nucleotide binding and effector interactions, and a helical domain. The guanine nucleotide resides in a cleft between the two domains, and the helical domain is engaged in slowing down GDP release in the inactive state. Mutational analyses [8] have identified two amino acids in the α-subunit as being essential for its intrinsic GTPase activity: a glutamine residue in the N-terminus (at position 204 in Gαi1 and 227 in Gαs), and a conserved arginine (at position 201 in Gαs, and 178 in Gαi1).
Biological Activities of ras Genes
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
Steven Sorscher, Axel Schönthal, Arthur S. Alberts, Judy L. Meinkoth, James R. Feramisco
How can ras proteins control cellular growth and regulate expression of proteins associated with tumorigenic transformation? Extensive analyses have shown that the ras proteins are GTP-binding proteins with GTPase activity. Their enzymatic activity is controlled by specific types of regulatory proteins, the GTPase-activating proteins (GAP) as well as by posttranslational modification events. This functional similarity to G proteins (enzymes that serve to transmit signals generated by ligand interactions with specific cell surface receptors into changes in intracellular functions) suggested a role for ras proteins in intracellular signal transduction pathways. Indeed, it has been shown that overexpression of ras protein stimulates the transcription of several genes whose protein products are thought to play crucial roles in the control of cell growth (for reviews see Chapters 5, 6, 10, 21, and 22 and References 91 and 92).
Quercetin acts via the G3BP1/YWHAZ axis to inhibit glycolysis and proliferation in oral squamous cell carcinoma
Published in Toxicology Mechanisms and Methods, 2023
Meng Hu, Hong-yan Song, Ling Chen
A protein that may contribute to oral squamous cell carcinoma is GTPase-activating protein SH3 domain-binding protein 1 (G3BP1), which is overexpressed in many types of cancers (Li et al. 2020; Omer et al. 2020). Such overexpression is linked to poor survival in esophageal squamous carcinoma, non-small cell lung cancer, and gastric cancer (Zhang et al. 2007; Min et al. 2015; Zheng et al. 2019). In gastric cancer cells, G3BP1 induces proliferation and metastasis, while at the same time repressing apoptosis (Xiong et al. 2019). Conversely, G3BP1 underexpression leads to slower growth and greater apoptosis of oral squamous cell carcinoma cells (Xu et al. 2013). In fact, G3BP1 may be a biomarker of oral squamous cell carcinoma cell proliferation and apoptosis, as well as prognosis of patients with the disease (Hu et al. 2021). These observations suggest that G3BP1 helps drive oral squamous cell carcinoma, but the pathways involved remain poorly understood.
The roles and mechanisms of G3BP1 in tumour promotion
Published in Journal of Drug Targeting, 2019
Cong-Hui Zhang, Jun-Xia Wang, Mei-Lian Cai, Rongguang Shao, Hong Liu, Wu-Li Zhao
Ras is a small GTP-binding protein that is regulated by GTPase activating protein. GAP hydrolyses GTP into GDP and subsequently induces Ras-GTP inactivation [20]. G3BP1 was initially found by coprecipitation with the SH3 domain of Ras-GAP, a negative regulator of Ras [21]. The coprecipitation relied on Ras activation [22]. Furthermore, the interaction between G3BP1 and Ras-GAP is likely to regulate the activity of Ras downstream signalling molecules, such as extracellular regulated protein kinase (ERK) and MEK. Transient knockdown of G3BP1 suppressed the growth of colon cancer HCT116 cells by inhibiting Ras and downstream kinase activity, such as that of ERK and MEK [23]. These findings suggest that G3BP1 promotes tumour cell proliferation by regulating the Ras signalling pathway. Indeed, G3BP1 downregulation blocks Ras signalling. In addition, coprecipitation of G3BP1 and Ras-GAP can be prevented by the polypeptides 38GAP or GAP161, the sequences of which were derived from the G3BP1-interacting sequence of Ras-GAP.
Small GTPases in platelet membrane trafficking
Published in Platelets, 2019
Tony G. Walsh, Yong Li, Andreas Wersäll, Alastair W. Poole
The purpose of this review was to explore the roles of the Rab, Arf and Ras families of small guanosine triphosphatases (GTPases) with respect to platelet membrane trafficking events (exocytosis, endocytosis and granule biogenesis) and provide speculative arguments on trafficking roles that other platelet expressed GTPases may assume. Categorised on the basis of sequence homology, these three families of GTPases comprise over 130 proteins, which function as molecular switches cycling between an inactive ‘GDP-bound’ form to an active ‘GTP-bound’ form to regulate specific effector proteins which can also function beyond membrane trafficking events. The GTPase activities of these proteins are regulated by two classes of proteins; guanine nucleotide exchange factors (GEFs) which promote the GTP-bound form, whereas GTPase-activating proteins (GAPs) accelerate GTP hydrolysis to inactivate the GTPase [18]. Another key feature of these GTPases are the membrane-targeting sequences within the C-termini of Rab and Ras GTPases and N-termini of Arf GTPases, which control their membrane association and biological activity through lipid modifications [19]. We acknowledge there are other important regulators of vesicle trafficking in platelets, such as cytoskeletal proteins, kinases such as PKCα and PKD2, the large GTPase dynamin and dynamin-related protein 1 that are not discussed here, but we refer the reader to a number of relevant publications [20–25]. We also recommend a recent review on RhoGTPases in platelets, which details roles for specific Rho family members with respect to platelet secretion [26].