共查询到20条相似文献,搜索用时 31 毫秒
1.
I I Babichenko 《Biulleten' eksperimental'no? biologii i meditsiny》1989,107(2):245-247
The indirect peroxidase-labeled antibody method was used to localize insulin receptors in the median eminence of rat hypothalamus. For experiments the rabbit antisera against synthetic peptides correspond to the deduced amino acid sequences of alpha- and beta-subunits of human placenta insulin receptor used as the first sera. The antisera were produced by prof. N. Yanaihara. Results have shown that after intraventricular injection of 1 U insulin the electron dense particles of DAB reaction were distributed on the surface membrane of tanycytes and axon terminals in the median eminence of hypothalamus. The functional properties of revealed receptors corresponded to IGF-1 receptors. Results support the hypothesis of central regulatory action of insulin in brain by its interaction with central IGF-1 receptors on the membrane of neuroependymal elements in the median eminence of hypothalamus. 相似文献
2.
The effect of a cholecystokinin (CCK) preparation on the secretion of corticosterone when injected intraperitoneally and intraventricularly was studied in the rat. Both routes of injections produced pronounced elevation of plasma corticosterone levels, but the minimum effective dose by intraventricular injection was 10 mU/rat and that by intraperitoneal injection 2 U/100 g, or approximately 5 U/rat. Although the effect was observed in vagotomized rats, CCK did not affect the pituitary gland itself. It was inferred that CCK acts directly or indirectly on CRF neurones in the brain. Since CCK preparation used in the present experiments was contaminated with motilin, the effect of synthetic motilin on the adrenocortical secretion was also examined. However, no stimulatory effect was found following intraventricular injection of this peptide. 相似文献
3.
Haley GE Flynn FW 《American journal of physiology. Regulatory, integrative and comparative physiology》2008,294(5):R1760-R1767
Neurokinin 3 receptor (NK3R) signaling has an integral role in the stimulated oxytocin (OT) and vasopressin (VP) release in response to hyperosmolarity and hypotension. Peripheral injections of cholecystokinin (CCK) receptor agonists for the CCK-A (sulfated CCK-8) and CCK-B (nonsulfated CCK-8) receptors elicit an OT release in rat. It is unknown whether NK3R contributes to this endocrine response. Freely behaving male rats were administered an intraventricular pretreatment of 250 or 500 pmol of SB-222200, a specific NK3R antagonist, or 0.15 M NaCl before an intraperitoneal or intravenous injection of CCK-8 (nonsulfated or sulfated) or 0.15 M NaCl. Blood samples were taken before intraventricular treatment and 15 min after intraperitoneal or intravenous injection, and plasma samples were assayed for OT and VP concentration. Intraperitoneal injection of both nonsulfated and sulfated CCK-8 significantly increased plasma OT levels and had no effect on plasma VP levels. Intravenous injection of sulfated CCK-8 stimulated an increase in plasma OT levels and did not alter plasma VP levels. However, intravenous injection of nonsulfated CCK-8 stimulated a significant increase in plasma levels of both OT and VP. No other studies have demonstrated CCK-8-stimulated release of VP in rat. NK3R antagonist did not alter baseline levels of either hormone. However, pretreatment of NK3R antagonist significantly blocked the CCK-stimulated release of OT in all CCK treatment groups and blocked VP release in response to intravenous injection of nonsulfated CCK-8. Therefore, central NK3R signaling is required for OT and VP release in response to CCK administration. 相似文献
4.
M Arluison M P Martres P Sokoloff 《Comptes rendus des séances de la Société de biologie et de ses filiales》1982,176(1):23-29
An attempt to localize dopaminergic receptors in the rat neostriatum by high-resolution radioautography was realized using intracerebral injections of the new ligand (antagonist) 3H-domperidone. In tissue regions located far from the injection site, the weaker diffuse radioautographic reaction permitted us to observe the existence of clusters of silver grains over some cerebral structures. The specificity of this type of labelling was tested using intraperitoneal injections of large amounts of haloperidol in order to block the studied receptors. Thus, we observed specific labelling over some nerve terminals as well as a low number of synaptic contact of the asymmetric type (however some synapses of the symmetric type were also labelled). These result agree with our previous work (1), and confirm the existence of dopaminergic synapses in the rat caudate-putamen. 相似文献
5.
We used fluorescence correlation spectroscopy to examine the binding of insulin, insulin-like growth factor 1 (IGF1) and anti-receptor antibodies to insulin receptors (IR) and IGF1 receptors (IGF1R) on individual 2H3 rat basophilic leukemia cells. Experiments revealed two distinct classes of insulin binding sites with K(D) of 0.11 nM and 75 nM, respectively. IGF1 competes with insulin for a portion of the low-affinity insulin binding sites with K(D) of 0.14 nM and for the high-affinity insulin binding sites with K(D) of 10 nM. Dissociation rate constants of insulin and IGF1 were determined to be 0.015 min(-1) and 0.013 min(-1), respectively, allowing estimation of ligand association rate constants. Combined, our results suggest that, in addition to IR and IGF1R homodimers, substantial numbers of hybrid IR-IGF1R heterodimers are present on the surface of these cells. 相似文献
6.
Recent evidence suggests that, after binding insulin, insulin receptors (IR) interact with specialized, cholesterol-containing, membrane microdomains and components of the actin cytoskeleton. Using single particle tracking techniques, we examined how binding of insulin, depletion of membrane cholesterol and disruption of actin filaments affect the lateral diffusion of individual quantum dot-labeled native IR on live rat basophilic leukemia 2H3 cells. We also examined the effects of similar treatments on IR clustering and multivalent insulin binding on these cells using both photon counting histogram analysis and polarization-based fluorescence resonance energy homo-transfer imaging. Our analyses indicate that binding of insulin to IR on these cells is multivalent, involving at least two insulin molecules per IR as labeling concentrations approach 1μM. Insulin binding also reduces lateral diffusion of IR and the size of membrane compartments accessed by IR. For IR that have not bound insulin, lateral diffusion of IR and the size of membrane compartments accessed by IR increase after disrupting actin filaments or depleting membrane cholesterol. However, clustering of insulin-occupied IR is reduced only by disrupting actin filaments or by fixing cells with paraformaldehyde prior to exposure to insulin, but not by depleting membrane cholesterol. Thus, it appears that, although restriction of IR lateral diffusion on these cells is sensitive to both actin filament dynamics and membrane cholesterol content, clustering of insulin-occupied IR primarily involves an actin-dependent mechanism. 相似文献
7.
Protein-tyrosine phosphatases (PTPases) play a key role in maintaining the steady-state tyrosine phosphorylation of the insulin receptor (IR) and its substrate proteins such as insulin receptor substrate 1 (IRS-1). However, the PTPase(s) that inactivate IR and IRS-1 under physiological conditions remain unidentified. Here, we analyze the subcellular distribution in rat adipocytes of several PTPases thought to be involved in the counterregulation of insulin signaling. We found that the transmembrane enzymes, protein-tyrosine phosphatase (PTP)-alpha and leukocyte common antigen-related (LAR), were detected predominantly in the plasma membrane and to a lesser extent in the heavy microsomes, a distribution similar to that of insulin receptor. PTP-1B and IRS-1 were present in light microsomes and cytosol, whereas SHPTP2/Syp was exclusively cytosolic. Insulin induced a redistribution of PTP-alpha from the plasma membrane to the heavy microsomes in a parallel fashion with the receptor. The distribution of PTP-1B in the light microsomes from resting adipocytes was similar to that of IRS-1 as determined by sucrose velocity gradient fractionation. Analysis of the catalytic activity of partially purified rat adipocyte PTP-alpha and LAR and recombinant PTP-1B showed that all three PTPases dephosphorylate IR. When a mix of IR/IRS-1 was used as a substrate, PTP-1B was particularly effective in dephosphorylating IRS-1. Considering that IR and IRS-1 can be dephosphorylated in internal membrane compartments from rat adipocytes (Kublaoui, B., Lee, J., and Pilch, P.F. (1995) J. Biol. Chem. 270, 59-65) and that PTP-alpha and PTP-1B are the respective PTPases in these fractions, we conclude that these PTPases are responsible for the counterregulation of insulin signaling there, whereas both LAR and PTP-alpha may act upon cell surface insulin receptors. 相似文献
8.
J W Burgess I Wada N Ling M N Khan J J Bergeron B I Posner 《The Journal of biological chemistry》1992,267(14):10077-10086
In a previous study, we showed that the rat hepatic insulin receptor (IR) kinase of endosomes (ENs) was transiently activated to levels exceeding those of plasma membrane (PM) receptors following insulin injection. Phosphatase treatment of EN receptors abolished IR kinase activation implicating beta-subunit autophosphorylation as a mediator of the activation process (Khan, M. N., Baquiran, G., Brule, C., Burgess, J., Foster, B., Bergeron, J. J. M., and Posner, B. I. (1989) J. Biol. Chem. 264, 12931-12940). In the present study, the phosphotyrosine (PY) content of the IR beta-subunit in PM and ENs was estimated by two different methods. In one method, direct in vivo labeling with 32Pi followed by receptor immunoprecipitation was carried out. In the second method, immunoblotting with antibodies against the submembrane domain of the IR beta-subunit, encompassing residue 960 (alpha 960), and with antibodies against PY (alpha PY) was used to determine the content of PY/beta-subunit in PM and ENs following injection of insulin. By both methods, it was found that the PY content of PM IR was significantly greater than that of IR in ENs. With doses of 1.5 micrograms of insulin/100 g body weight (50% receptor occupancy) or 15 micrograms/100 g body weight (receptor saturation), the PY/beta-subunit of PM IR attained a level 2.0 to 2.5-fold of that observed for the IR of ENs. Surprisingly, the IR of ENs incorporated 3 to 5 times more PY/beta-subunit than those of PM consequent to autophosphorylation. Exogenous IR kinase activity (poly(Glu:Tyr)) in PM changed only slightly with insulin dose. In contrast, EN receptors exhibited a dose-dependent increase in kinase activity coincident with the decrease in PY/beta-subunit levels. A comparison of the proportion of receptor and kinase activity immunoprecipitated by alpha PY both before and after autophosphorylation indicated that ENs but not PM contained a small population of lightly phosphorylated but highly activated receptors. Since Thr12-Lys (IR kinase residues 1142-1153) efficiently inhibited IR autophosphorylation of both PM and EN receptors, Tris phosphorylation of beta-subunit regulatory tyrosines was unlikely. These results may be explicable by a dephosphorylation-dependent activation of IR kinase, as seen with the src family of tyrosine kinases. 相似文献
9.
Differential modulation of the tyrosine phosphorylation state of the insulin receptor by IRS (insulin receptor subunit) proteins. 总被引:1,自引:0,他引:1
B T Solow S Harada B J Goldstein J A Smith M F White L Jarett 《Molecular endocrinology (Baltimore, Md.)》1999,13(10):1784-1798
In response to insulin, tyrosine kinase activity of the insulin receptor is stimulated, leading to autophosphorylation and tyrosine phosphorylation of proteins including insulin receptor subunit (IRS)-1, IRS-2, and Shc. Phosphorylation of these proteins leads to activation of downstream events that mediate insulin action. Insulin receptor kinase activity is requisite for the biological effects of insulin, and understanding regulation of insulin receptor phosphorylation and kinase activity is essential to understanding insulin action. Receptor tyrosine kinase activity may be altered by direct changes in tyrosine kinase activity, itself, or by dephosphorylation of the insulin receptor by protein-tyrosine phosphatases. After 1 min of insulin stimulation, the insulin receptor was tyrosine phosphorylated 8-fold more and Shc was phosphorylated 50% less in 32D cells containing both IRS-1 and insulin receptors (32D/IR+IRS-1) than in 32D cells containing only insulin receptors (32D/IR), insulin receptors and IRS-2 (32D/IR+IRS-2), or insulin receptors and a form of IRS-1 that cannot be phosphorylated on tyrosine residues (32D/IR+IRS-1F18). Therefore, IRS-1 and IRS-2 appeared to have different effects on insulin receptor phosphorylation and downstream signaling. Preincubation of cells with pervanadate greatly decreased protein-tyrosine phosphatase activity in all four cell lines. After pervanadate treatment, tyrosine phosphorylation of insulin receptors in insulin-treated 32D/IR, 32D/ IR+IRS-2, and 32D/IR+IRS-1F18 cells was markedly increased, but pervanadate had no effect on insulin receptor phosphorylation in 32D/IR+IRS-1 cells. The presence of tyrosine-phosphorylated IRS-1 appears to increase insulin receptor tyrosine phosphorylation and potentially tyrosine kinase activity via inhibition of protein-tyrosine phosphatase(s). This effect of IRS-1 on insulin receptor phosphorylation is unique to IRS-1, as IRS-2 had no effect on insulin receptor tyrosine phosphorylation. Therefore, IRS-1 and IRS-2 appear to function differently in their effects on signaling downstream of the insulin receptor. IRS-1 may play a major role in regulating insulin receptor phosphorylation and enhancing downstream signaling after insulin stimulation. 相似文献
10.
Slaaby R Schäffer L Lautrup-Larsen I Andersen AS Shaw AC Mathiasen IS Brandt J 《The Journal of biological chemistry》2006,281(36):25869-25874
Insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) are both from the same subgroup of receptor tyrosine kinases that exist as covalently bound receptor dimers at the cell surface. For both IR and IGF-IR, the most described forms are homodimer receptors. However, hybrid receptors consisting of one-half IR and one-half IGF-IR are also present at the cell surface. Two splice variants of IR are expressed that enable formation of two isoforms of the IGF-IR/IR hybrid receptor. In this study, these two splice variants of hybrid receptors were studied with respect to binding affinities of insulin, insulin-like growth factor I (IGF-I), and insulin-like growth factor II (IGF-II). Unlike previously published data, in which semipurified receptors have been studied, we found that the two hybrid receptor splice variants had similar binding characteristics with respect to insulin, IGF-I, and IGF-II binding. We studied both semipurified and purified hybrid receptors. In all cases we found that IGF-I had at least 50-fold higher affinity than insulin, irrespective of the splice variant. The binding characteristics of insulin and IGF-I to both splice variants of the hybrid receptors were similar to classical homodimer IGF-IR. 相似文献
11.
L.Charles Murrin 《Life sciences》1982,31(10):971-980
Studies of the ontogeny of dopamine and neuroleptic receptors in the central nervous system of the rat were carried out using 3H-spiperone as ligand. It was demonstrated that intraperitoneal injections can be successfully used to label these receptors in rat pups up to at least 30 days of age. The time course and characteristics of 3H-spiperone binding in the brain of 5, 15 and 30 day old rat pups were determined and found to include appropriate regional distribution, saturability and appropriate pharmacology. The developmental pattern of 3H-spiperone binding paralleled what has been seen using techniques. In addition preliminary autoradiographic studies describe the neuroanatomical pattern of dopamine receptor ontogeny in the striatum. 相似文献
12.
C Pierre-Eugene P Pagesy TT Nguyen M Neuillé G Tschank N Tennagels C Hampe T Issad 《PloS one》2012,7(7):e41992
Background
In diabetic patients, the pharmacokinetics of injected human insulin does not permit optimal control of glycemia. Fast and slow acting insulin analogues have been developed, but they may have adverse properties, such as increased mitogenic or anti-apoptotic signaling. Insulin/IGF1 hybrid receptors (IR/IGF1R), present in most tissues, have been proposed to transmit biological effects close to those of IGF1R. However, the study of hybrid receptors is difficult because of the presence of IR and IGF1R homodimers. Our objective was to perform the first study on the pharmacological properties of the five marketed insulin analogues towards IR/IGF1R hybrids.Methodology
To study the effect of insulin analogues on IR/IGF1R hybrids, we used our previously developed Bioluminescence Resonance Energy Transfer (BRET) assay that permits specific analysis of the pharmacological properties of hybrid receptors. Moreover, we have developed a new, highly sensitive BRET-based assay to monitor phophatidylinositol-3 phosphate (PIP3) production in living cells. Using this assay, we performed a detailed pharmacological analysis of PIP3 production induced by IGF1, insulin and insulin analogues in living breast cancer-derived MCF-7 and MDA-MB231 cells.Results
Among the five insulin analogues tested, only glargine stimulated IR/IGF1R hybrids with an EC50 that was significantly lower than insulin and close to that of IGF1. Glargine more efficiently stimulated PIP3 production in MCF-7 cells but not in MDA-MB231 cells as compared to insulin. In contrast, glargine metabolites M1 and M2 showed lower potency for hybrid receptors stimulation, PIP3 production, Akt and Erk1/2 phosphorylation and DNA synthesis in MCF-7 cells, compared to insulin.Conclusion
Glargine, possibly acting through IR/IGF1R hybrids, displays higher potency, whereas its metabolites M1 and M2 display lower potency than insulin for the stimulation of proliferative/anti-apoptotic pathways in MCF-7 cells. 相似文献13.
Zammit VA 《Biochemical Society transactions》2000,28(2):103-109
This review illustrates how the use of several in vitro and in vivo techniques was necessary to show that the effect of insulin on hepatic triacylglycerol (TAG) secretion in the rat depends on the prior physiological state of the animal. The effect of insulin was always inhibitory when cultured cells were used, irrespective of the physiological state of the donor rats. By contrast, when perfused livers were used, insulin stimulated TAG secretion by livers isolated from fed, normoinsulinaemic rats, but inhibited it in livers from fasted or streptozotocin diabetic animals. This switch in insulin action was also shown to occur in vivo in experiments that involved the liver-specific targeting of both insulin (delivered within liposomes) and labelled fatty acids (delivered as cholesteryl esters within very-low-density lipoprotein remnants) in awake, unrestrained rats during a euglycaemic clamp. It is concluded that observations obtained with perfused liver preparations are more representative of the actual changes that occur in vivo with respect to the effects of insulin on hepatic TAG secretion. 相似文献
14.
F De Venanzi F Pe?a O Jiménez H De Alvarado 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1976,152(1):47-51
Isolated perfused fed rat livers spontaneously liberated glucose and orthophosphate to the medium; 24-hr fasted rat livers did not exhibit these phenomena. In perfused fed rat livers, glucagon (2 mug) increased glucose output and promoted orthophosphate incorporation. In perfused fed rat livers, insulin (250 or 500 mU) inhibited the spontaneous liberation of glucose and orthophosphate. Comparable doses of insulin significantly reduced the glucagon (2 mug)-induced increase in glucose output from perfused fed rat liver, but did not affect orthophosphate uptake by the organ. 相似文献
15.
Insulin receptors in rat liver plasma membranes contain two alpha- and two beta-subunits held together by interchain disulphide bonds ([alpha beta]2 receptors). Affinity-labelled receptors were digested with chymotrypsin or elastase and then exposed to dithiothreitol before solubilization from membranes and SDS/polyacrylamide-gel electrophoresis. This resulted in partial reduction and isolation of Mr-225,000 alpha beta, Mr-200,000 alpha 1 beta, Mr-165,000 alpha beta 1 and Mr-145,000 alpha 1 beta 1 receptor halves containing intact (alpha, beta) or degraded (alpha 1, beta 1) subunits. The ability to identify half-receptor complexes containing intact or degraded subunits made it possible to assay each subunit simultaneously for insulin-induced proteolysis in isolated plasma membranes or during perfusion of rat liver in situ with insulin. In liver membranes, insulin binding increased the fraction of receptors containing degraded alpha-subunits to about one-third of the total population during 2 h of incubation at 23 degrees C. beta-Subunit proteolysis increased only minimally during this time. Plasma membranes isolated from livers perfused with insulin at 37 degrees C contained degraded alpha-subunits but only intact beta-subunits, showing that insulin induced cell-surface proteolysis of the binding, but not the kinase, domain of its receptor. Since previous observations [Lipson, Kolhatkar & Donner (1988) J. Biol. Chem 263, 10495-10501] have shown that receptors containing degraded alpha-subunits are internalized but do not recycle, it is possible that cell-surface degradation may play a role in the regulation of insulin-receptor number in hepatic tissue. Proteolysis of the beta-subunit is not a likely mechanism by which receptor-kinase activity may be attenuated under physiological conditions. 相似文献
16.
Wang H Liu Z Li G Barrett EJ 《American journal of physiology. Endocrinology and metabolism》2006,291(2):E323-E332
The pathways by which insulin exits the vasculature to muscle interstitium have not been characterized. In the present study, we infused FITC-labeled insulin to trace morphologically (using confocal immunohistochemical methods) insulin transport into rat skeletal muscle. We biopsied rectus muscle at 0, 10, 30, and 60 min after beginning a continuous (10 mU x min(-1) x kg(-1)), intravenous FITC-insulin infusion (with euglycemia maintained). The FITC-insulin distribution was compared with that of insulin receptors (IR), IGF-I receptors (IGF-IR), and caveolin-1 (a protein marker for caveolae) in skeletal muscle vasculature. We observed that muscle endothelium stained strongly for FITC-insulin within 10 min, and this persisted to 60 min. Endothelium stained more strongly for FITC-insulin than any other cellular elements in muscle. IR, IGF-IR, and caveolin-1 were also detected immunohistochemically in muscle endothelial cells. We further compared their intracellular distribution with that of FITC-insulin in cultured bovine aortic endothelial cells (bAECs). Considerable colocalization of IR or IGF-IR with FITC-insulin was noted. There was some but less overlap of IR or IGF-IR or FITC-insulin with caveolin-1. Immunoprecipitation of IR coprecipitated caveolin-1, and conversely the precipitation of caveolin-1 brought down IR. Furthermore, insulin increased the tyrosine phosphorylation of caveolin-1, and filipin (which inhibits caveolae formation) blocked insulin uptake. Finally, the ability of insulin, IGF-I, and IGF-I-blocking antibody to diminish insulin transport across bAECs grown on transwell plates suggested that IGF-IR, in addition to IR, can also mediate transendothelial insulin transit. We conclude that in vivo endothelial cells rapidly take up and concentrate insulin relative to plasma and muscle interstitium and that IGF-IR, like IR, may mediate insulin transit through endothelial cells in a process involving caveolae. 相似文献
17.
The insulin receptor (IR), the insulin-like growth factor-1 receptor (IGF1R), and the insulin/IGF1 hybrid receptors (hybR) are homologous transmembrane receptors. The peptide ligands, insulin and IGF1, exhibit significant structural homology and can bind to each receptor via site-1 and site-2 residues with distinct affinities. The variants of the Iridoviridae virus family show capability in expressing single-chain insulin/IGF1 like proteins, termed viral insulin-like peptides (VILPs), which can stimulate receptors from the insulin family. The sequences of VILPs lacking the central C-domain (dcVILPs) are known, but their structures in unbound and receptor-bound states have not been resolved to date. We report all-atom structural models of three dcVILPs (dcGIV, dcSGIV, and dcLCDV1) and their complexes with the receptors (μIR, μIGF1R, and μhybR), and probed the peptide/receptor interactions in each system using all-atom molecular dynamics (MD) simulations. Based on the nonbonded interaction energies computed between each residue of peptides (insulin and dcVILPs) and the receptors, we provide details on residues establishing significant interactions. The observed site-1 insulin/μIR interactions are consistent with previous experimental studies, and a residue-level comparison of interactions of peptides (insulin and dcVILPs) with the receptors revealed that, due to sequence differences, dcVILPs also establish some interactions distinct from those between insulin and IR. We also designed insulin analogs and report enhanced interactions between some analogs and the receptors. 相似文献
18.
M Morris W B Campbell W A Pettinger 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1976,151(1):101-104
The effects of centrally administered autonomic drugs and hypertonic saline on renin release were studied in the conscious rat. A 0.3 mug intraventricular dose of isoproterenol, which is one-thirtieth of the intraperitoneal dose required to stimulate renin release, induced the release of renin into the systemic circulation. Norepinephrine had no effect on renin release in the same dose range. Hypertonic saline and carbachol suppressed renin release. Alterations in renin release were preceded by a reciprocal change in blood pressure. These results suggest a central nervous system site for sodium, beta-adrenergic, and cholinergic receptors in altering renin release and blood pressure. 相似文献
19.
J M Ruiz-Albusac J A Zueco E Velázquez J F Alvarez J M Mato E Blázquez 《FEBS letters》1989,258(2):281-284
We have used isolated rat hepatocytes to study whether the insulin-induced reduction of its own receptors may modify the transduction of hormone signals by changes in the content of a glycosyl-phosphatidylinositol. Both subsequent insulin binding and glycosyl-phosphatidylinositol concentrations markedly decreased as a function of time and insulin concentration during preincubation of hepatocytes with insulin. The modifications observed in insulin binding were due to changes in receptor concentration. These results show that insulin regulates both the number of its own receptors and glycosyl-phosphatidylinositol concentrations in target cells, which may be of interest in many pathophysiological situations. 相似文献
20.
Jongsoon Lee Masaya Miyazaki Giulio R. Romeo Steven E. Shoelson 《The Journal of biological chemistry》2014,289(28):19769-19777
Complementary surfaces are buried when peptide hormones, growth factors, or cytokines bind and activate cellular receptors. Although these extended surfaces provide high affinity and specificity to the interactions, they also present great challenges to the design of small molecules that might either mimic or antagonize the process. We show that the insulin receptor (IR) and downstream signals can be activated by targeting a site outside of its ligand-binding domain. A 24-residue peptide having the IR transmembrane (TM) domain sequence activates IR, but not related growth factor receptors, through specific interactions with the receptor TM domain. Like insulin-dependent activation, IR-TM requires that IR have a competent ATP-binding site and kinase activation loop. IR-TM also activates mutated receptors from patients with severe insulin resistance, which do not respond to insulin. These results show that IR can be activated through a pathway that bypasses its canonical ligand-binding domain. 相似文献