Macvector mutagenesis1/30/2024 ![]() The exact molecular and cellular mechanisms that lead to the observed phenotypes are still largely unclear ( Prior et al., 2012). For example, in Noonan syndrome, NRAS or KRAS can be mutated at various positions along their coding sequences in the germline. These syndromes are also characterized by a hyperactivation of the Ras/MAPK-signaling pathway. A different mutational spectrum is found in RASopathies, developmental syndromes that are characterized by facio-cutaneous malformations, heart developmental and neurodevelopmental defects, as well as a predisposition to certain cancers ( Schubbert et al., 2007). These oncogenic lesions render Ras transforming and tumorigenic, as they leave Ras constitutively GTP bound and therefore ready to overdrive in particular the Ras/MAPK pathway, which critically controls cell division and other oncogenic processes. Since the seminal publication of Scheffzeck et al., it is well understood that hot-spot mutations in codons 12, 13, and 61 ( Scheffzek et al., 1997), which account for >99% of Ras mutations ( Prior et al., 2012), primarily compromise its GAP-dependent hydrolase activity. However, recent progress encourages the pursuit of specific Ras protein inhibitors ( Spiegel et al., 2014). Ras hyperactivation is a hallmark of cancer and has long been considered to be pharmacologically intractable ( Cox et al., 2014). Its principal steady-state localization is the plasma membrane, from where most of Ras signaling emerges ( Hancock., 2003). The small GTPase Ras is dynamically anchored to cellular membranes. The next challenge is to develop drugs that block the formation of Ras nanoclusters and to find out if they have the potential to be used to treat cancer. ![]() Solman et al.'s findings reveal a new way that Ras can be activated in cancer cells. The mutations probably alter the way that Ras sits in the membrane, which in turn changes the way it interacts with other proteins and the membrane so that more Ras nanoclusters form. The experiments show that several mutations that alter a region of Ras called the ‘switch III region’ moderately increase the activity of Ras. used microscopy and biochemical techniques to study the effects of some of the less common mutations on Ras activity in human cells. Other mutations in the gene that encodes Ras are also found in cancer cells, but these are less common and it is not clear how they alter the activity of the protein. However, in many cancer cells, Ras is active all the time due to mutations that occur in three ‘hotspots’ within its gene. In normal cells, other proteins control when Ras is active. The tight packing of the proteins in these nanoclusters increases the amount of Ras in the membrane locally, which allows Ras to interact with other proteins more efficiently to promote growth and cell division. Ras congregates at the membrane that surrounds the cell and can assemble into clusters (called nanoclusters) that each contain six to eight Ras proteins. ![]() Many human cancers have mutations in a gene that encodes a protein called Ras, which promotes cell growth and division by controlling the activities of other proteins. Cancer is a disease that develops when cells within the body acquire genetic mutations that allow them to grow and divide rapidly.
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