The Src Family Kinase Yes Triggers Hyperosmotic Activation of the Epidermal Growth Factor Receptor and CD95

Reinehr, Roland; Becker, Stephan; Höngen, Andrea; Häussinger, Dieter

doi:10.1074/jbc.m401519200

Cited by 73 publications

(106 citation statements)

References 47 publications

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“…This, however, is cell type-specific and depends on the efficacy of RVI mechanisms (73,83,85) . In rat hepatocytes, hyperosmotic cell shrinkage triggers ligand-independent and Src family kinase Yes-dependent CD95 activation and subsequent CD95 trafficking to the plasma membrane, thereby sensitizing hepatocytes toward CD95 ligand (CD95L)-induced apoptosis or even executing apoptosis when the hyperosmotic challenge is strong enough (10,73,86) . In contrast, in HSCs, proapoptotic stimuli such as CD95L lead to a c-Src-mediated EGFR activation and subsequent cell proliferation (94) .…”

Section: Src Family Kinases and Apoptosismentioning

confidence: 99%

“…In line with the findings that oxidative stress contributes to the cholestatic state after hyperosmotic hepatocyte shrinkage is the observation that hydrophobic bile acids not only induce cholestasis but also oxidative stress via NOX activation (75,76) . This hyperosmolarityinduced and NOX-mediated reactive oxygen species (ROS) formation leads to an activation of the Src family kinases Yes and Fyn (10) and of c-Jun N-terminal kinase (JNK) (73) , whereas c-Src is not activated by hyperosmolarity (10) . It was shown in the perfused rat liver that the hyperosmotic retrieval of Bsep and Mrp2 from the canalicular membrane is sensitive to the inhibition of Fyn, whereas Yes and JNK are not involved in hyperosmolarity-induced changes in bile acid transporter localization (21) .…”

Section: Downstream Dual Activation Of Both Erks and P38mentioning

confidence: 99%

“…All these different challenges trigger the activation of the Src family kinase Yes in liver parenchymal cells (10,54,89) . The detailed mechanisms of hyperosmolarity-induced ROS formation have been discussed in detail above (see also Figure 2A) and resemble those triggered by CD95L (89) or hydrophobic bile acids (75,76) .…”

Section: Src Family Kinases and Apoptosismentioning

confidence: 99%

“…Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR) also can induce Src family kinase phosphorylation (1) and vice versa , Src family kinases can (trans)activate the EGFR (9,10) . Recent data suggest that c-Src directly interacts with hepatitis C virus (HCV)-encoded proteins.…”

Section: Introductionmentioning

confidence: 99%

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The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver

Reinehr

Sommerfeld

Häussinger

2013

BioMolecular Concepts

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Abstract:The Src family kinases Yes, Fyn, and c-Src play a pivotal role in regulating diverse liver functions such as bile flow, proteolysis, apoptosis, and proliferation and are regulated by anisoosmotic cell volume changes, death receptor ligands, and bile acids. For example, cell swelling leads to an integrin-sensed and focal adhesion kinase-mediated activation of c-Src-triggering choleresis, proteolysis inhibition, regulatory volume decrease via p38 MAPK and proliferation via the activation of the epidermal growth factor receptor and extracellular regulated kinases 1 and 2. In contrast, hepatocyte shrinkage generates an almost instantaneous oxidative stress response that triggers the activation of c-Jun N-terminal kinase and the Src family kinases Fyn and Yes. Whereas Fyn activation mediates cholestasis, Yes triggers CD95 activation and apoptosis. This review will discuss the role of Src family kinases in the regulation of liver function with emphasis on their role in osmo-signaling and bile acid signaling.

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Section: Src Family Kinases and Apoptosismentioning

confidence: 99%

Section: Downstream Dual Activation Of Both Erks and P38mentioning

confidence: 99%

Section: Src Family Kinases and Apoptosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver

Reinehr

Sommerfeld

Häussinger

2013

BioMolecular Concepts

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“…5). Ligand-dependent and -independent CD95 activation in hepatocytes is a complex process that finally results in CD95 trafficking from the cellular interior to the plasma membrane, subsequent formation of the death-inducing signaling complex (DISC), and eventually apoptosis (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Cd95mentioning

confidence: 99%

Amplification of CD95 Activation by Caspase 8-induced Endosomal Acidification in Rat Hepatocytes

Reinehr

Sommerfeld

Keitel

et al. 2008

Journal of Biological Chemistry

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Although in rat hepatocytes CD95 is predominantly located inside the cell with almost undetectable immunostaining at the plasma membrane, the addition of CD95-ligand (CD95L) induces hepatocyte apoptosis, which is preceded by a targeting and activation of intracellularly localized CD95 to the plasma membrane including formation of the death-inducing signaling complex. This process involves an NADPH oxidase-dependent generation of reactive oxygen species (ROS) through a ceramide-and protein kinase C-dependent pathway, which leads to an activating phosphorylation of p47 phox . The mechanisms underlying CD95L-induced ceramide formation were addressed in the present study. It was found that CD95L lowered within seconds the apparent vesicular pH from 6.0 to 5.7 in a fluorescein isothiocyanate-dextran-accessible endosomal compartment, which was previously shown to contain acidic sphingomyelinase, and decreased N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide fluorescence, suggestive for an increase of cytosolic [Cl ؊ ]. Bafilomycin or 4,4-diisothiocyanostilbene-2,2-disulfonic acid disodium salt largely abolished the CD95L-induced endosomal acidification, ceramide formation, and downstream events, such as p47 phox phosphorylation, ROS formation, CD95 activation, and apoptosis. These responses were also abolished after knock-down of acidic sphingomyelinase in rat hepatocytes. Interestingly, caspase 8 inhibitors abolished these CD95L-induced signaling events, including the increase in cytosolic [Cl ؊ ], endosomal acidification, ceramide formation, and ROS generation as well as CD95 targeting to the plasma membrane and CD95 activation. The data suggest that CD95L initiates a rapid caspase 8-dependent endosomal acidification, which triggers ceramide-dependent ROS formation as an upstream event of trafficking of intracellularly stored CD95 to the plasma membrane. It is concluded that a rapid caspase 8 activation in response to CD95L signals to intracellularly stored CD95, which becomes activated and targeted to the plasma membrane. This autoamplification of CD95-activation is required for apoptosis induction. CD952 (Apo-1/Fas) belongs to the death receptor family and plays an important role in apoptosis induction in many cell types. In hepatocytes, CD95 is mainly located within the cellular interior and can either be activated after ligation with its natural ligand (CD95L) or in a ligand-independent way by hydrophobic bile salts or hyperosmotic cell shrinkage (Refs. 1-4; for review, see Ref. 5). Ligand-dependent and -independent CD95 activation in hepatocytes is a complex process that finally results in CD95 trafficking from the cellular interior to the plasma membrane, subsequent formation of the death-inducing signaling complex (DISC), and eventually apoptosis (1-12).In hepatocytes, proapoptotic stimuli such as CD95 ligand (CD95L), hydrophobic bile salts, or hyperosmotic cell shrinkage induce a rapid oxidative stress (ROS) response (2, 4), which triggers a Yes-dependent but ligand-independent activation of the epiderm...

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Role of Ion Transport in Control of Apoptotic Cell Death

Läng

Hoffmann

2012

Comprehensive Physiology

131

132

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Cell shrinkage is a hallmark and contributes to signaling of apoptosis. Apoptotic cell shrinkage requires ion transport across the cell membrane involving K + channels, Cl − or anion channels, Na + /H + exchange, Na + ,K + ,Cl − cotransport, and Na + /K + ATPase. Activation of K + channels fosters K + exit with decrease of cytosolic K + concentration, activation of anion channels triggers exit of Cl − , organic osmolytes, and HCO 3 − . Cellular loss of K + and organic osmolytes as well as cytosolic acidification favor apoptosis. Ca 2+ entry through Ca 2+ ‐permeable cation channels may result in apoptosis by affecting mitochondrial integrity, stimulating proteinases, inducing cell shrinkage due to activation of Ca 2+ ‐sensitive K + channels, and triggering cell‐membrane scrambling. Signaling involved in the modification of cell‐volume regulatory ion transport during apoptosis include mitogen‐activated kinases p38, JNK, ERK1/2, MEKK1, MKK4, the small G proteins Cdc42, and/or Rac and the transcription factor p53. Osmosensing involves integrin receptors, focal adhesion kinases, and tyrosine kinase receptors. Hyperosmotic shock leads to vesicular acidification followed by activation of acid sphingomyelinase, ceramide formation, release of reactive oxygen species, activation of the tyrosine kinase Yes with subsequent stimulation of CD95 trafficking to the cell membrane. Apoptosis is counteracted by mechanisms involved in regulatory volume increase (RVI), by organic osmolytes, by focal adhesion kinase, and by heat‐shock proteins. Clearly, our knowledge on the interplay between cell‐volume regulatory mechanisms and suicidal cell death is still far from complete and substantial additional experimental effort is needed to elucidate the role of cell‐volume regulatory mechanisms in suicidal cell death. © 2012 American Physiological Society. Compr Physiol 2:2037‐2061, 2012.

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The Src Family Kinase Yes Triggers Hyperosmotic Activation of the Epidermal Growth Factor Receptor and CD95

Cited by 73 publications

References 47 publications

The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver

The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver

Amplification of CD95 Activation by Caspase 8-induced Endosomal Acidification in Rat Hepatocytes

Role of Ion Transport in Control of Apoptotic Cell Death

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