Summary of known actions of activated ras-p21 in cells, beginning (top, left) when a growth factor binds to its cell receptor

Summary of known actions of activated ras-p21 in cells, beginning (top, left) when a growth factor binds to its cell receptor. This results in activation of intracytoplasmic tyrosine kinase (TK) activity on the receptor that binds to the adapter grb-2 protein that concurrently binds to and activates the guanine nucleotide exchange factor (GNEF), SOS. This, in turn, induces ras-p21 to exchange GDP for GTP, resulting in its activation. ras-p21 is bound to the inner cell membrane by a covalent farnesyl moiety attachment in thioether linkage to Cys 186. In its GTP-bound form ras-p21 binds to a number of other target proteins. One of these is GAP (GTPase activating protein) that induces GTPase activity in ras-p21 resulting in hydrolysis of GTP to GDP cycling ras-p21 into the inactive state. Both GAP and SOS may also be involved as a target in ras signaling, hence the question mark below the GAP box. Activated ras-p21 also binds to and activates raf (top middle of the figure), a 74 kDa Ser/Thr kinase protein that, in turn, activates the kinase cascade in which it activates MEK that finally activates ERK (MAP-2K in the figure) that is involved in cytoskeletal rearrangements in the cytosol and which shuttles into the nucleus where it activates the nuclear transcription factor, fos, that forms a heterodimeric complex with the nuclear transcription factor, jun. The latter protein is activated by another kinase, jun-N-terminal kinase (JNK), that occurs on a separate pathway called the stress-activated protein (SAP) pathway. As explained in the text, oncogenic ras-p21 directly activates JNK/jun that circumvents the normal, regulated wild-type ras-p21-activated pathways (right side of the figure). ras-p21 also interacts directly with phosphoinositol-3-hydroxy kinase (PI3K, left side of the figure) and induces activation of phospholipase C (PLC); both of these proteins cause increases in the second messenger molecule, inositol triphosphate (IP3) and diacylglycerol (DAG); the former induces calcium mobilization while the latter induces activation of protein kinase C (PKC) that is especially critical to the oncogenic ras-p21 pathway. In the nucleus, the fos-jun complex, also called AP1, induces transcription of many pro-mitogenic proteins including cyclins and possible the nuclear skeletal proteins called nuclear matrix proteins (NMP’s); other nuclear proteins, like myc, also transcriptionally active, are also often activated in this process. Anti-oncogene proteins, such as p53, also become activated. This protein blocks transcription of pro-mitotic proteins and induces apoptosis in transformed cells.

Publication

Novel peptides from the RAS-p21 and p53 proteins for the treatment of cancer. () Wilbur B. Bowne, et al. Cancer Ther. ;5B:331-344. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

Disease mentions