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The signal that starts the MAPK/ERK pathway is the binding of extracellular mitogen to a cell surface receptor. This allows a Ras protein (a Small GTPase) to swap a GDP molecule for a GTP molecule, flipping the "on/off switch" of the pathway. The Ras protein can then activate MAP3K (e.g., Raf), which activates MAP2K, which activates MAPK.
These pathways can effectively convey stimuli from the cell membrane (where many MAP3Ks are activated) to the nucleus (where only MAPKs may enter) or to many other subcellular targets. [citation needed] In comparison to the three-tiered classical MAPK pathways, some atypical MAP kinases appear to have a more ancient, two-tiered system.
Another tumor-lysing virus that specifically targets tumor cells with an activated Ras pathway is a type II herpes simplex virus (HSV-2) based agent, designated FusOn-H2. [28] Activating mutations of the Ras protein and upstream elements of the Ras protein may play a role in more than two-thirds of all human cancers, including most metastatic ...
The MAP kinase-kinase, which activates ERK, was named "MAPK/ERK kinase" . [5] Receptor-linked tyrosine kinases, Ras, Raf, MEK, and MAPK could be fitted into a signaling cascade linking an extracellular signal to MAPK activation. [6] See: MAPK/ERK pathway. Transgenic gene knockout mice lacking MAPK1 have major defects in early development. [7]
GAP eventually returns Ras to its inactive state. Activation of Ras has the potential to initiate three signaling pathways downstream of Ras: Ras→Raf→MAP kinase pathway, PI3 kinase pathway, and Ral pathway. Each pathway leads to the activation of transcription factors which enter the nucleus to alter gene expression. [9]
Third, downstream effectors of mitogenic signaling are often mutated in cancer cells. An important mitogenic signaling pathway in humans is the Ras-Raf-MAPK pathway. Mitogenic signaling normally activates Ras, a GTPase, that then activates the rest of the MAPK pathway, ultimately expressing proteins that stimulate cell cycle progression.
Akt/PKB signalling pathway; AMPK signalling pathway; cAMP-dependent pathway; Eph/ephrin signalling pathway; Hedgehog signalling pathway; Hippo signalling pathway; Insulin signal transduction pathway; JAK-STAT signalling pathway; MAPK/ERK signalling pathway; mTOR signalling pathway; Nodal signalling pathway; Notch signalling pathway; PI3K/AKT ...
This recruits adapter protein GRB2 which binds to SOS exchange factors, that bind and activate Ras. Ras/MAPK pathways is activated by the intracellular calcium that binds to the ilimaquinone domain (IQ) on Ras-GRF1. [2] Activated Ras can go on to activate Raf/Mek/Erk kinases which can mediate the activation of CREB transcription factors.