Ral insulin receptor substrates (IRSs) (69), at the same time as other scaffold proteins

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asked Sep 10 in Database by eyenote2 (390 points)
IRS proteins are composed of an NH2 -terminal pleckstrin <a href="https://www.medchemexpress.com/Decoyinine.html">Decoyinine Technical Information</a> homology (PH) domain adjacent to a phosphotyrosine-binding (PTB) domain, and followed by a tail containing several tyrosine and Ser/Thr phosphorylation web-sites (75). The Tyr phosphorylation sites coordinate downstream signaling cascades by binding the SH2 domains present in frequent effector proteins, including enzymes (the phosphoinositide 3-kinase, PI3K; the phosphatase SHP2; or the tyrosinekinase Fyn) or adapters (SOCS1, SOCS-3, GRB2, and other people) (70, 74). By contrast, the precise serine phosphorylation with the IRS-1/2 by the c-Jun N-terminal kinase (JNK1) as well as other protein kinases inhibits insulin-stimulated tyrosine phosphorylation, which correlates closely with insulin resistance (76). Likewise, the ubiquitin-mediated degradation of IRS-1/2 also promotes insulin resistance (77). Nonetheless, the agonists that raise IRS-2 expression via cAMP production and CREB activation boost insulin signaling (78). The synapse would be the major locus of cell ell communication in the nervous system. It has been reported that IR was co-expressed with the insulin receptor tyrosine-kinase   substrate p58/53 (IRSp53) in the synapse-rich molecular layer and in the granule cell layer with the cerebellum, at the same time as inside the synapses on the cultured hippocampal neuron, which recommended that these molecules may very well be part of an insulin-dependent signaling pathway at the post-synaptic apparatus (79). IRSp53, which is phosphorylated upon stimulation with insulin (80, 81), is a crucial issue in cytoskeleton reorganization that mediates neurite outgrowth (82), getting also involved in numerous neurodegenerative disorders (83), because IRSp53-deficient animals record cognitive deficits within the contextual fear-conditioning paradigm (84). The association of IRS proteins and PI3K triggers the activation of this enzyme, which phosphorylates an inositol phospholipid in the plasma membrane, named PI (4,5)P2 , to PI (3,4,5)P3 , which recruits each the Ser/Thr kinase PDK (3-phosphatidylinositoldependent protein kinase) and protein kinase B (PKB or Akt) for the plasma membrane, where Akt is activated by PDK1- and PDK2-mediated phosphorylation (85). This signaling pathway is antagonized by the action in the phospholipid phosphatases PTEN or SHIP2.   Akt phosphorylates various substrates, including TSC2 (tuberous sclerosis complicated, tuberin), which finally activates theFrontiers in Endocrinology | Neuroendocrine ScienceOctober 2014 | Volume five | Article 161 |Bl quez et al.Relationships among T2DM and ADFIGURE 2 | Transduction of signals and biological actions induced by insulin or IGF-1 through their receptor or through their hybrid receptors.mammalian target of rapamycin (mTOR) and gives a direct link among insulin si.Ral insulin receptor substrates (IRSs) (69), at the same time as other scaffold proteins (70), which initiate divergent signal transduction pathways (71). Likewise, following the binding of insulin, aggregated IRs are quickly internalized in to the cell by a process that a minimum of in element involves coated pits and vesicles (72). It has been suggested that aggregation or internalization could be vital for insulin signaling (73). The internalized IRs can then be degraded or recycled back for the cell membrane. Most insulin responses are mediated by IRS-1 and IRS-2. IRS-1 controls body development and peripheral insulin action, when IRS2 regulates brain development, body weight handle, glucose homeostasis, and female fertility (74). IRS proteins are composed of an NH2 -terminal pleckstrin homology (PH) domain adjacent to a phosphotyrosine-binding (PTB) domain, and followed by a tail containing several tyrosine and Ser/Thr phosphorylation sites (75).

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