1.More than a hundred proteins comprise the RAS superfamily of small GTPases. Th
ID: 3166055 • Letter: 1
Question
1.More than a hundred proteins comprise the RAS superfamily of small GTPases. This family can be divided into RAS, RHO, RAB, RAN, ARF, and RAD subfamilies, with each shown to play distinct roles in human cells in both health and disease. The RAS subfamily has a well-established role in human cancer with the three genes, HRAS, KRAS, and NRAS being commonly mutated in tumors Mutations of RAS have been isolated that have dominant-negative activity (that is, they block signaling by the normal, endogenous G protein). Suggest a possible mechanism for how a dominant-negative mutation in the SH2 domain of Grb-2 can decrease Ras signaling. »Explanation / Answer
SH2 forms a part of the shc family, where, shc means an SH2 domain where there would be proteins related to the collagen receptors. When there is tyrosine phosphorylation of the Shc proteins, there there occurs Shc-Grb2 complex formation, there will be transformation of the cells resulting in over expression of the p185 signals leading to an oncogenes signal transformation from p185.
In this pathway, Grb2 plays an important role. It can play dual roles, one where it would be binding with the SH3 domain along with the Sos complex and the other is the binding with the shc complex via the SH2 domain. Dominant negative mutants occur when there is a deletion of the SH3 domain resulting in a dominant negative mutation that would be competing with the Grb2 association with the SOS complex or this mutation would be blocking the oncogenic pathway of signals of the p185 that has been activated.
For Ras activation, the Shc-Grb2-Sos complex requires to be formed for activation of the receptors, EGF receptors, or the insulin receptors. As a result, from the activated p185 there would be signals sent to the Ras complex. These dominant negative mutants would be capable to the p185 that has been activated by mutation and the Shc that has been phosphorylated by tyrosine and as a result, these complexes will not be able to associate with the SOS component. This results in inhibition of activation of Ras.
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