IndraLab
Statements
MAP2K1 is active.
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"Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 ras activation leads to raf and subsequently mek activation. Phospholipide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf."
"Cot proteins were used in an in vitro kinase assay using mek as a substrate. Samples were analyzed by western blotting. As seen in the cascade activity assay only wild-type cot was active against mekregulation of cot is of great interest to the signaling field since the cot/mek/erk pathway potentially plays a role in the etiology of inflammatory autoimmune diseases."
"Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf."
"We analyzed the ability of mp1 to bind to mek1, erk1, and to itself, and the regulation of these interactions. Gel filtration of cell lysates revealed two major mp1 peaks: a broad high molecular weight peak and a 28 kda complex. An mp1 mutant that lost mek1 binding no longer enhanced rasv12-stimulated erk1 activity, and functioned as a dominant negative, consistent with the concept that mp1 function depends on facilitating these oligomerizations."
MAP2K1 is kinase-active.
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"Despite remarkable progress in dissecting the signaling pathways that are crucial for the metabolic effects of insulin, the molecular basis for the specificity of its cellular actions is not fully understood. One clue might lie in the spatial and temporal aspects of signaling. Recent evidence suggests that signaling molecules and pathways are localized to discrete compartments in cells by specific protein interactions. Also, the rapid termination of tyrosine or lipid phosphorylation by phosphatases or serine kinases might tightly control the strength of a signaling pathway, thus determining its effect on growth, differentiation and metabolism. Insulin is the most potent anabolic hormone known, promoting the synthesis and storage of carbohydrates, lipids and proteins and inhibiting their degradation and release back into the circulation. Decreased secretion of insulin, coupled with resistance to its actions, results in type 2 diabetes, a devastating disease that is reaching epidemic proportions [1]. Even in the absence of diabetes, insulin resistance is often associated with central obesity, hypertension, polycystic ovarian syndrome, dyslipidemia and atherosclerosis. At the cellular level, insulin action is characterized by diverse effects, including changes in vesicle trafficking, stimulation of protein kinases and phosphatases, promotion of cellular growth and differentiation and activation or repression of transcription. This complexity suggests that insulin action must involve multiple signaling pathways that diverge at or near the activation of its tyrosine kinase receptor. In fact, it is likely that even individual effects of the hormone require multiple signaling inputs. Evidence is emerging that the coordination of these pathways might be governed by their intracellular compartmentalization or duration of action. Here, we consider how temporal and spatial aspects of signal transduction play a crucial role in determining the specificity of insulin action, focusing on signal initiation from the receptor that is spatially segregated into discrete domains of the plasma membrane, as well as the mechanisms that determine the duration of individual signaling pathways. Together, these factors help to differentiate insulin from other hormones that share some of the same overall signaling properties. Divergent signaling pathways are initiated by insulin receptor substrates. The insulin receptor is a tyrosine kinase that catalyzes the phosphorylation of several intracellular substrates, including the insulin receptor substrate (IRS) proteins [2], GAB-1 [3], Shc [4], APS [5], p60DOK [6], SIRPS [7] and c-Cbl [8] (Fig. 1). Each of these substrates recruits a distinct subset of signaling proteins containing Src homology 2 (SH2) domains, which interact specifically with sequences surrounding the phosphotyrosine residue. Moreover, each of these substrates can be confined to distinct locations in the cell by specific sequences that direct interactions with other proteins or lipids. Most attention in the field of insulin receptor substrates has focused on the IRS family of proteins. Mice lacking the IRS-1 protein are insulin resistant but do not develop overt diabetes [9,10]. By contrast, animals lacking IRS-2 exhibit both impaired glucose tolerance and diabetes [11], which appears to result from a defect in insulin secretion as well as insulin resistance, presumably owing to decreased b-cell proliferation in the pancreas in the face of increased demand for insulin. Despite the similarity in structure and function, the apparent differences in phenotype between IRS1 and IRS2 knockout mice underscore a specific signaling specificity that probably results from their tissue distribution, subcellular location, activation–inactivation kinetics and combinatorial interactions with downstream effectors [12]. The tyrosine phosphorylation of IRS family members generates docking sites for sev..."
MAP2K1 is inactive.
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