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Ras genes encode proteins of the Ras superfamily, which are important molecular switches in signal transduction pathways. Ras proteins are involved in cell adhesion, apoptosis, cell migration, cytoskeletal integrity, cell proliferation, and, when unregulated, neoplasia.

activation/inactivation : amplification : DGKzeta : GAPs : GEFs : mutations : Rab: Ras superfamily : Ras : RasGAP : RasGRP : Rho : superfamily :

The superfamily includes Ras, Rho, and Rab families. The Rho family includes Rho-GTPase. [] inactive and active Ras molecular switch [] Once activated by binding to GTP (Rho-GTP), Rho GTPases interact with cellular target effector proteins to drive axonal guidance, reorganization of the actin cytoskeleton (morphogenesis, cell polarity, cell movement, and cytokinesis), regulation of gene expression, chemotaxis, cell cycle progression, oncogenic transformation, and epithelial wound repair.

Ras is a small GTPase (G-protein), a regulatory GTP hydrolase that cycles between activated (RAS-GTP) and inactivated (RAS-GDP) conformations. [] 3D inactive and active Ras molecular switch []Ras is activated by guanine exchange factors (GEFs) such as CDC25, SOS1 and SOS2, and SDC25 in yeast. The GEFs are activated by mitogenic signals and through feedback from Ras itself.

Ras is inactivated by GTPase-activating proteins (GAPs), including RasGAP. This activating protein increases the rate of GTP hydrolysis and converts Ras from the active GTP-bound conformation to the inactive GDP-bound form (releasing Pi).

Diacylgycerol kinase zeta (DGKzeta) regulates factors that promote activity of the oncogene product, Ras, the activity of which must be precisely regulated lest abnormal cellular proliferation result. An estimated 30% of human tumors have an activating mutation of the Ras gene. Guanine nucleotide exchange factors (GEFs) activate Ras by facilitating GTP binding. Abnormally high levels of the nucleotide exchange factor, RasGRP (RAS-GAP) can lead to malignant transformation. RasGRP has a diacylglycerol (DAG)-binding domain and its exchange factor activity depends on local availability of the signaling molecule DAG. Diacylglycerol kinases(DGKs) remove DAG from the cell by converting DAG to PA. DGKzeta, but not other DGKs, can completely eliminate Ras activation induced by RasGRP, and diacylglycerol kinase activity is required for this mechanism.

Ras is attached to the cell membrane by prenylation. It normally functions in pathways that couple growth factor receptors to downstream mitogenic effectors that are involved in cell proliferation or cellular differentiation. Ras activates several pathways, of which the mitogen-activated protein MAP kinase pathway is important. MAPKs transmit signals downstream to other protein kinases and gene regulatory proteins.

Mutations of Ras proto-oncogenes are common → H-RAS, N-RAS, and K-RAS oncogenes. Inappropriate activation of the Ras gene plays a key role in signal transduction, proliferation, and malignant transformation. Oncogenes such as p210BCR-ABL and the growth receptor erbB are located upstream of Ras, so their signals will transduce through Ras should they be constitutively activated. The tumour suppressor gene NF1 encodes a RAS-GAP (Ras-GRP), and its mutation in neurofibromatosis renders Ras less likely to be inactivated.

Point mutations can transform Ras into oncogenes such that its GTPase reaction can no longer be stimulated by GAP, increasing the half life of active Ras-GTP mutants. Mutations that prevent GTP hydrolysis favor constitutive activation as RAS-GTP, RasD. The commonest mutations are at the 12 (Gly→Val) → GAP insensitive, and the 61 positions → stabilizing against GTP hydrolysis.

Ras amplification occurs only occasionally in tumours. Unfortunately, the sequence differences between Ras proto-oncogenes and Ras oncogenes are so slight (typically single amino acid changes) that drug targetting abnormal Ras will prove very difficult.

activation/inactivation : amplification : DGKzeta : GAPs : GEFs : mutations : Rab: Ras superfamily : Ras : RasGAP : RasGRP : Rho : superfamily :


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