Raf-1 and B-Raf promote protein kinase C θ interaction with BAD

Hindley, Alison D.; Kölch, Walter

doi:10.1016/j.cellsig.2006.08.004

Cited by 21 publications

(19 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bad is a proapoptotic protein whose activity is inhibited when it is phosphorylated. 13,14 The results also show an increase in the antiapoptotic regulatory protein, cFLIP, in L3 but no change in the antiapoptotic species Bax inhibitor-I (BI-I; a densitometric analysis of replicates from 4 livers by ANOVA revealed P Ͻ 0.04 for cFLIP in L3 versus L2 and L1, P Ͻ 0.01 for pBAD in L3 versus L2 and L1, and P Ͼ 0.3 for Bax in L3 versus L2 or L1). [15][16][17][18] These data indicate that an increasing hepatocellular globular accumulation of the a1AT mutant Z polymerized protein is associated with not only increased caspase activation but also an in- crease in antiapoptotic proteins.…”

Section: Resultsmentioning

confidence: 77%

Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model

2007

View full text Add to dashboard Cite

Alpha-1-antitrypsin (a1AT) deficiency is caused by homozygosity for the a1AT mutant Z gene and occurs in 1 in 2000 births. The Z mutation confers an abnormal conformation on the protein, resulting in an accumulation within the endoplasmic reticulum of hepatocytes rather than appropriate secretion. The accumulation of the mutant protein is strikingly heterogeneous within the liver. Homozygous ZZ children and adults have an increased risk of chronic liver disease, which is thought to result from this variable intracellular accumulation of the a1AT mutant Z protein. Previous reports have suggested that autophagy, mitochondrial injury, apoptosis, and other pathways may be involved in the mechanism of hepatocyte injury, although the interplay of these mechanisms in vivo is unclear. In this study, we examine a well-characterized in vivo model of a1AT mutant Z liver injury, the PiZ mouse, to better understand the pathways involved in this disease. The results show an increase in the stimulation of the apoptotic cascade in hepatocytes, the magnitude of which strongly correlates to the absolute amount of the a1AT mutant Z protein accumulated within the individual cell. Increases in apoptotic regulatory proteins are also detected. Conclusion: These data, combined with previous work, permit for the first time the construction of a hypothetical hepatocellular injury cascade for this disease involving mitochondrial injury, caspase activation, and apoptosis, which takes into account the heterogeneous nature of the mutant Z protein accumulation within the liver. Further development of this hypothetical cascade will focus future research on this and other metabolic liver diseases. T he genetic disease alpha-1-antitrypsin (a1AT) deficiency is caused by homozygosity for the a1AT mutant Z gene and occurs in 1 in 2000 births. 1 The Z mutation confers an abnormal conformation on the nascent polypeptide, resulting in an accumulation of the mutant protein within the endoplasmic reticulum (ER) of hepatocytes rather than the appropriate, highly efficient secretion of the wild-type (WT) protein. Homozygous, ZZ individuals have an increased risk of chronic liver disease and hepatocellular carcinoma resulting from this intracellular accumulation of the a1AT mutant Z protein.Studies of the a1AT mutant Z protein molecule have shown that the nascent polypeptide has a tendency to form unique protein homopolymers. 1,2 Although this loop-sheet insertion mechanism of a1AT mutant Z protein polymerization, in which the reactive site loop of one molecule inserts into a surface groove in a neighboring molecule, does not involve the formation of covalent bonds, physical-chemical studies of these polymers suggest that this conformation is highly favored. It is proposed and supported by some published data that the liver injury in humans with a1AT deficiency is directly related to the hepatic accumulation of the polymerized a1AT mutant Z protein. [3][4][5] Our laboratory and others have reported a series of studies that have begun to examine the mechani...

show abstract

Section: Resultsmentioning

confidence: 77%

Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model

2007

View full text Add to dashboard Cite

show abstract

“…V600E) is observed broadly in solid cancers of multiple primary sites (59,60). Leukemias of lymphoid origin express B-Raf, and other than the recent discovery of hairy cell leukemia, mutations of the BRAF gene are very rare, suggesting a fundamental and conserved role in T cell leukemia and possibly normal T cell function (61)(62)(63)(64)(65)(66)(67). Although there are few studies that focus on the importance of B-Raf to T cell physiology, it has been shown that MAPK signaling during T cell development progression beyond the CD4-CD8 double positive stage requires B-Raf, and rescue experiments with B-Raf can restore proliferation through MAPK signaling in anergic T cells (40,67).…”

Section: Discussionmentioning

confidence: 99%

B-Raf Regulation of Integrin α4β1-mediated Resistance to Shear Stress through Changes in Cell Spreading and Cytoskeletal Association in T Cells

Brown

Khalili

Rodriguez-Cruz

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…Aside from its ability to phosphorylate key downstream proteins such as Erk and Bad, Raf-1 has also been proposed to protect cells by serving as a scaffolding protein (54). Deletion of the Raf-1 gene has been associated with increased activity of apoptosis signaling kinase-1 (Ask-1), an event that does not require Raf-1 catalytic activity (55).…”

Section: Roles and Mechanisms Of Raf-1 And Pi 3-kinase/akt Signaling mentioning

confidence: 99%

Inhibition of Raf-1 Alters Multiple Downstream Pathways to Induce Pancreatic β-Cell Apoptosis

Alejandro¹,

Johnson

2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

The serine threonine kinase Raf-1 plays a protective role in many cell types, but its function in pancreatic ␤-cells has not been elucidated. In the present study, we examined whether primary ␤-cells possess Raf-1 and tested the hypothesis that Raf-1 is critical for ␤-cell survival. Using reverse transcriptase-PCR, Western blot, and immunofluorescence, we identified Raf-1 in human islets, mouse islets, and in the MIN6 ␤-cell line. Blocking Raf-1 activity using a specific Raf-1 inhibitor or dominant-negative Raf-1 mutants led to a time-and dose-dependent increase in cell death, assessed by real-time imaging of propidium iodide incorporation, TUNEL, PCR-enhanced DNA laddering, and Caspase-3 cleavage. Although the rapid increase in apoptotic cell death was associated with decreased Erk phosphorylation, studies with two Mek inhibitors suggested that the classical Erkdependent pathway could explain only part of the cell death observed after inhibition of Raf-1. An alternative Erk-independent pathway downstream of Raf-1 kinase involving the pro-apoptotic protein Bad has recently been characterized in other tissues. Inhibiting Raf-1 in ␤-cells led to a striking loss of Bad phosphorylation at serine 112 and an increase in the protein levels of both Bad and Bax. Together, our data strongly suggest that Raf-1 signaling plays an important role regulating ␤-cell survival, via both Erk-dependent and Bad-dependent mechanisms. Conversely, acutely inhibiting phosphatidylinositol 3-kinase Akt had more modest effects on ␤-cell death. These studies identify Raf-1 as a critical anti-apoptotic kinase in pancreatic ␤-cells and contribute to our understanding of survival signaling in this cell type.A reduction in pancreatic ␤-cell survival is a critical pathogenic event in type 1 diabetes, type 2 diabetes, and rare monogenic forms of the disease. Moreover, increased ␤-cell death has been implicated in the failure of clinical islet transplantation (1-3). Several kinases have been investigated for their possible roles in ␤-cell survival, with PI 3 3-kinase and Akt receiving the most attention to date (4 -8). Transgenic mice that overexpress constitutively active Akt in their ␤-cells are protected against streptozotocin-induced diabetes (9, 10) and overexpression of constitutively active Akt protects INS-1 cells from free fatty acid-induced apoptosis (11). However, mice with an 80% reduction in islet Akt activity did not show increased apoptosis or reduced ␤-cell mass (12, 13), suggesting the possibility that other kinases may contribute to ␤-cell survival.The Ras-Raf-mitogen-activated protein kinase cascade mediates pro-survival signals in many cell types. However, this signaling pathway remains understudied in pancreatic ␤-cells. Members of this pathway are found in human and mouse islets, as well as in ␤-cell lines (14 -17). The Raf kinase is a critical hub in this cascade, as it integrates multiple upstream signals and controls several downstream effectors. All three Raf isoforms (A-Raf, B-Raf, and C-Raf/Raf-1) share a common structu...

show abstract

Raf-1 and B-Raf promote protein kinase C θ interaction with BAD

Cited by 21 publications

References 51 publications

Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model

Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model

B-Raf Regulation of Integrin α4β1-mediated Resistance to Shear Stress through Changes in Cell Spreading and Cytoskeletal Association in T Cells

Inhibition of Raf-1 Alters Multiple Downstream Pathways to Induce Pancreatic β-Cell Apoptosis

Contact Info

Product

Resources

About