Ras subfamily

• OMIM: 164 790

• MGI: 97376

Ras (Rat sarcoma ) is a proto-oncogene that encodes a so-called small G- protein ( monomeric). It was described in 1981 by American molecular biologist Robert Allan Weinberg.

Function

Ras is a central member of various signal transduction pathways that regulate growth and differentiation processes. As monomeric GTP -binding protein, it assumes the function of a regulated molecular switch can be turned on or off with the cellular processes. Ras switches between two states, where it has either GTP bound ( RASG ) or the GTP is hydrolyzed to GDP ( Ras ). The molecular basis of this switching function is based on different protein conformations in binding of GTP or GDP. Ras can interact only in the GTP- bound state with other signaling proteins ( called effectors ), then in turn mediate the signal transduction. Since both the intrinsic GTP hydrolysis ( GTPase activity ) and the intrinsic nucleotide are generally very slow processes, the life of the active and inactive state of Ras on nucleotide exchange factors ( guanine - nucleotide exchange factor GEF) and GTPase -activating proteins ( CAP) controlled.

Signal transduction pathway

For example, the receptor tyrosine kinase ( RTK) signal transduction pathway. The binding of a ligand to a receptor tyrosine kinase (RTK) whose causes dimerization, autophosphorylation of the receptor which has the result. The phosphorylated tyrosines on the RTK now serve as a docking site for the cytosolic adapter protein Grb2, which in turn is constitutively associated with the Ras -GEF SOS ( Son Of Sevenless ). Autophosphorylation of the receptor thus leading to the recruitment of the protein complex to the membrane Grb2/SOS and thus in the immediate vicinity of Ras. SOS now activated Ras, which allows the release of GDP and subsequent exchange with GTP, which is present in approximately ten fold higher concentration in the cytosol. Activated Ras -GTP can then bind the effector Raf kinase. The membrane recruitment leads to the activation of Raf, partly due to a conformational change. Active Raf kinase can now activate in turn the MEK kinase by phosphorylation. Active MEK in turn phosphorylates and activates the Erk kinase. Active Erk ultimately passes into the nucleus, where it can be activated by phosphorylation of a number of transcription factors.

Cancer Research

The fact that are found in 20 to 30 percent of all human tumors, point mutations in the ras gene, highlights the important role of Ras in the control of cell growth. These point mutations all lead to loss of GTPase activity of Ras, which can not be excited in the presence of GTPase activating proteins (GAP ). Since the change of the GTP-bound form is blocked to GDP- form, there is an accumulation of active Ras and thus to a permanent wachsstumsstimulierenden signal in the cell. Great efforts have been made ​​to understand the molecular basis of the switch function of Ras proteins and to develop anti- oncogenic Ras antitumor drugs. Some forms of Ras, such as KRAS even play a crucial role in whether certain oncology drugs are effective.