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41.
Effect of pathogenic cysteine mutations on FGFR3 transmembrane domain dimerization in detergents and lipid bilayers 总被引:2,自引:0,他引:2
Mutations in fibroblast growth factor receptors are known as the genetic basis of skeletal growth disorders. The mechanism of pathogenesis, as determined by mutation-induced changes in receptor structure, interactions, and function, is elusive. Here we study three pathogenic Cys mutations, associated with either thanatophoric dysplasia or achondroplasia, in the TM domain of fibroblast growth factor receptors 3 (FGFR3). We characterize the dimerization propensities of the mutant TM domains in detergents and in lipid bilayers, in the presence and absence of reducing agents, and compare them to previous measurements of wild-type. We find that the Cys mutations increase the propensity for dimerization in detergent, with the Cys370 mutant exhibiting the highest propensity for disulfide bond formation, the Cys371 mutant having an intermediate propensity, and Cys375 the lowest. Thus, disulfide bonds readily form in detergents, with efficiency that correlates with the severity of the phenotype. In lipid bilayers, however, the Cys370 mutant, which dimerizes strongly in detergent, behaves as the wild-type, suggesting that Cys370-mediated disulfide bonds do not form between the isolated TM domains in bilayers. Thus, the nature of the hydrophobic environment plays an important role in defining the structure and flexibility of transmembrane dimers. These results and previous findings from cellular studies lead us to propose a conformational flexibility mechanism of receptor stabilization as a basis for disregulated FGFR3 signaling in thanatophoric dysplasia and achondroplasia. 相似文献
42.
Wold LE Ceylan-Isik AF Fang CX Yang X Li SY Sreejayan N Privratsky JR Ren J 《Free radical biology & medicine》2006,40(8):1419-1429
Diabetic cardiomyopathy contributes to high morbidity and mortality in diabetic populations. It is manifested by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including oxidative stress. This study was designed to examine the effect of cardiac overexpression of the heavy metal scavenger metallothionein (MT) on cardiac contractile function, intracellular Ca(2+) cycling proteins, stress-activated signaling molecules and the myosin heavy chain (MHC) isozyme in diabetes. Adult male wild-type (FVB) and MT transgenic mice were made diabetic by a single injection of streptozotocin (STZ). Contractile properties were evaluated in cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt) and intracellular Ca(2+) fluorescence. Diabetes significantly depressed PS, +/-dL/dt, prolonged TPS, TR(90) and intracellular Ca(2+) clearing, elevated resting intracellular Ca(2+), reduced caffeine-induced sarcoplasmic reticulum Ca(2+) release and dampened stress tolerance at high stimulus frequencies. MT itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunctions. Diabetes enhanced expression of the AT(1) receptor, phospholamban, the p47(phox) NADPH oxidase subunit and poly(ADP-ribose) polymerase (PARP), depressed the level of SERCA2a, Na(+)-Ca(2+) exchanger and triggered a beta-MHC isozyme switch. All of these STZ-induced alterations with the exception of depressed SERCA2a and enhanced phospholamban were reconciled by MT. Collectively, these data suggest a beneficial effect of MT in the therapeutics of diabetic cardiomyopathy, possibly through a mechanism related to NADPH oxidase, PARP and MHC isozyme switch. 相似文献
43.
Beta-arrestin1 is an adapter/scaffold for many G protein-coupled receptors during mitogen-activated protein kinase signaling. Phosphorylation of beta-arrestin1 at position Ser-412 is a regulator of beta-arrestin1 function, and in the present study, we showed that insulin led to a time- and dose-dependent increase in beta-arrestin1 Ser-412 phosphorylation, which blocked isoproterenol- and lysophosphatidic acid-induced Ser-412 dephosphorylation and impaired ERK signaling by these G protein-coupled receptor ligands. Insulin treatment also led to accumulation of Ser-412-phosphorylated beta-arrestin1 at the insulin-like growth factor 1 receptor and prevented insulin-like growth factor 1/Src association. Insulin-induced Ser-412 phosphorylation was partially dependent on ERK as treatment with the MEK inhibitor PD98059 inhibited the insulin effect (62% reduction, p = 0.03). Inhibition of phosphatidylinositol 3-kinase by wortmannin did not have a significant effect (9% reduction, p = 0.41). We also found that the protein phosphatase 2A (PP2A) was in a molecular complex with beta-arrestin1 and that the PP2A inhibitor okadaic acid increased Ser-412 phosphorylation. Concomitant addition of insulin and okadaic acid did not produce an additive effect on Ser-412 phosphorylation, suggesting a common mechanism. Small t antigen specifically inhibited PP2A, and in HIRcB cells expressing small t antigen, beta-arrestin1 Ser-412 phosphorylation was increased, and insulin had no further effect. Insulin treatment caused increased beta-arrestin1 Ser-412 phosphorylation, which blocked mitogen-activated protein kinase signaling and internalization by beta-arrestin1-dependent receptors with no effect on beta-adrenergic receptor Gs-mediated cAMP production. These findings provide a new mechanism for insulin-induced desensitization of ERK activation by Galphai-coupled receptors. 相似文献
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Krig SR Frietze S Simion C Miller JK Fry WH Rafidi H Kotelawala L Qi L Griffith OL Gray JW Carraway KL Sweeney C 《Molecular cancer research : MCR》2011,9(10):1406-1417
Lrig1 is the founding member of the Lrig family and has been implicated in the negative regulation of several oncogenic receptor tyrosine kinases including ErbB2. Lrig1 is expressed at low levels in several cancer types but is overexpressed in some prostate and colorectal tumors. Given this heterogeneity, whether Lrig1 functions to suppress or promote tumor growth remains a critical question. Previously, we found that Lrig1 was poorly expressed in ErbB2-positive breast cancer, suggesting that Lrig1 has a growth-inhibitory role in this tumor type. However, breast cancer is a complex disease, with ErbB2-positive tumors accounting for just 25% of all breast cancers. To gain a better understanding of the role of Lrig1 in breast cancer, we examined its expression in estrogen receptor α (ERα)-positive disease which accounts for the majority of breast cancers. We find that Lrig1 is expressed at significantly higher levels in ERα-positive disease than in ERα-negative disease. Our study provides a molecular rationale for Lrig1 enrichment in ERα-positive disease by showing that Lrig1 is a target of ERα. Estrogen stimulates Lrig1 accumulation and disruption of this induction enhances estrogen-dependent tumor cell growth, suggesting that Lrig1 functions as an estrogen-regulated growth suppressor. In addition, we find that Lrig1 expression correlates with prolonged relapse-free survival in ERα-positive breast cancer, identifying Lrig1 as a new prognostic marker in this setting. Finally, we show that ErbB2 activation antagonizes ERα-driven Lrig1 expression, providing a mechanistic explanation for Lrig1 loss in ErbB2-positive breast cancer. This work provides strong evidence for a growth-inhibitory role for Lrig1 in breast cancer. 相似文献
46.
Alcohol use is common in adolescence, with a large portion of intake occurring during episodes of binging. This pattern of alcohol consumption coincides with a critical period for neurocognitive development and may impact decision-making and reward processing. Prior studies have demonstrated alterations in adult decision-making following adolescent usage, but it remains to be seen if these alterations exist in adolescence, or are latent until adulthood. Here, using a translational model of voluntary binge alcohol consumption in adolescents, we assess the impact of alcohol intake on risk preference and behavioral flexibility during adolescence. During adolescence (postnatal day 30–50), rats were given 1-hour access to either a 10% alcohol gelatin mixture (EtOH) or a calorie equivalent gelatin (Control) at the onset of the dark cycle. EtOH consuming rats were classified as either High or Low consumers based on intake levels. Adolescent rats underwent behavioral testing once a day, with one group performing a risk preference task, and a second group performing a reversal-learning task during the 20-day period of gelatin access. EtOH-High rats showed increases in risk preference compared to Control rats, but not EtOH-Low animals. However, adolescent rats did a poor job of matching their behavior to optimize outcomes, suggesting that adolescents may adopt a response bias. In addition, adolescent ethanol exposure did not affect the animals'' ability to flexibly adapt behavior to changing reward contingencies during reversal learning. These data support the view that adolescent alcohol consumption can have short-term detrimental effects on risk-taking when examined during adolescence, which does not seem to be attributable to an inability to flexibly encode reward contingencies on behavioral responses. 相似文献
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49.
Jamie C. Snyder Susan K. Brumfield Keshia M. Kerchner Tessa E. F. Quax David Prangishvili Mark J. Young 《Journal of virology》2013,87(4):2186-2192
Archaeal host cells infected by Sulfolobus turreted icosahedral virus (STIV) and Sulfolobus islandicus rod-shaped virus 2 (SIRV2) produce unusual pyramid-like structures on the cell surface prior to virus-induced cell lysis. This viral lysis process is distinct from known viral lysis processes associated with bacterial or eukaryal viruses. The STIV protein C92 and the SIRV2 protein 98 are the only viral proteins required for the formation of the pyramid lysis structures of STIV and SIRV2, respectively. Since SIRV2 and STIV have fundamentally different morphotypes and genome sequences, it is surprising that they share this lysis system. In this study, we have constructed a collection of C92/P98 chimeric proteins and tested their abilities, both in the context of virus replication and alone, to form pyramid lysis structures in S. solfataricus. The results of this study illustrate that these proteins are functionally homologous when expressed as individual chimeric proteins but not when expressed in the context of complete STIV infection. 相似文献
50.
William Finnegan Mingjia Yan Nicholas M. Holden Jamie Goggins 《The International Journal of Life Cycle Assessment》2018,23(9):1773-1787