Src Family Protein-tyrosine Kinases Alter the Function of PTEN to Regulate Phosphatidylinositol 3-Kinase/AKT Cascades

Lu, Yiling; Yu, Qinghua; Liu, Jue Hui; Zhang, Jinyi; Wang, Hongwei; Koul, Dimpy; McMurray, John S.; Fang, Xianjun; Yung, W. K. Alfred; Siminovitch, Kathy; Mills, Gordon B.

doi:10.1074/jbc.m303621200

Cited by 221 publications

(208 citation statements)

References 49 publications

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“…The NRG-1β/erbB2-dependent activation of Src/FAK observed here appears to be distinct from those pathways, as it was selectively suppressed by low concentrations of Src inhibitor or chronic treatment with an anti-erbB2 antibody. However, since higher concentrations of PP2 and anti-erbB2 partially inhibited NRG-1β-dependent phosphorylation of Akt (but not Erk), we cannot rule out the possibility that Src or FAK modulates PI3-kinase/Akt pathway in myocyte, similar to that reported in breast cancer cells and 293 cells [29,30]. The persistent activation of Akt and Erk in the presence of anti-erbB2 suggests that these pathways can be activated by erbB4 homodimerization alone.…”

Section: Discussionmentioning

confidence: 56%

Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes

Kuramochi

Guo

Sawyer

2006

Journal of Molecular and Cellular Cardiology

133

100

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Cardiac myocyte erbB2 expression is required for maintenance of normal cardiac structure and function, though its role in cardiac cellular physiology is incompletely understood. We tested the hypothesis that erbB2 signaling modulates focal adhesion formation via activation of a src/FAK pathway using adult rat ventricular myocytes in primary culture. The erbB ligand neuregulin-1β (NRG-1β) induced phosphorylation of Src at Y416 and Y215, and FAK at Y861. Using antibody and pharmacological inhibitor strategies, we found that FAK activation was erbB2-and Srcdependent, but independent of PI3-kinase/Akt pathway. Furthermore, NRG-1β stimulated the formation of a multiprotein complex between erbB2, FAK, p130 CAS and paxillin within 30 min, and induced lamellipodia with longitudinal elongation of the myocytes within days. The extension of lamellipodia resulted in restoration of cell-to-cell contact between isolated myocytes, allowing for synchronous beating. These effects of NRG-1β were prevented by a src inhibitor as well as an antibody to erbB2. These results suggest the potential role of NRG-1β/erbB2/Src/FAK signaling in the maintenance and repair of electrical and mechanical coupling in cardiomyocytes.

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Section: Discussionmentioning

confidence: 56%

Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes

Kuramochi

Guo

Sawyer

2006

Journal of Molecular and Cellular Cardiology

133

100

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“…A recent report demonstrated that activated Src reduces PTEN activity to in micelles, promotes Akt translocation to the plasma membrane, and increases tyrosine phosphorylation of PTEN (Lu et al, 2003). To test whether the status of PTEN phosphorylation was changed, we studied PTEN phosphorylation in anti-PTEN immunoprecipitates from insulin-treated cells by using anti-phosphotyrosine (4G10) and an antibody specific Ser/Thr phosphorylated PTEN ( Figure 5).…”

Section: Molecular Biology Of the Cell 352mentioning

confidence: 99%

“…About 16% of the total PTEN is oxidized by insulin stimulation. The higher value of insulin-mediated PTEN oxidation observed in the phosphatase activity assay (ϳ16%) compared with the value observed in the gel-shift assay (ϳ10%) may reflect the difference of sensitivity between these two methods, or it may reflect the fact that intermediate form of oxidized PTEN, which did not form intramolecular disulfide bonds, is included in the phosphatase activity assay.A recent report demonstrated that activated Src reduces PTEN activity to in micelles, promotes Akt translocation to the plasma membrane, and increases tyrosine phosphorylation of PTEN (Lu et al, 2003). To test whether the status of PTEN phosphorylation was changed, we studied PTEN phosphorylation in anti-PTEN immunoprecipitates from insulin-treated cells by using anti-phosphotyrosine (4G10) and an antibody specific Ser/Thr phosphorylated PTEN ( Figure 5).…”

mentioning

confidence: 99%

The Major Target of the Endogenously Generated Reactive Oxygen Species in Response to Insulin Stimulation Is Phosphatase and Tensin Homolog and Not Phosphoinositide-3 Kinase (PI-3 Kinase) in the PI-3 Kinase/Akt Pathway

Seo

Ahn

Lee

et al. 2005

MBoC

159

111

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(2) human neuroblastoma cell lines. When cells were stimulated with insulin, PI-3 kinase was activated in both cell lines, whereas the translocation of PDK-1 to the membrane fraction and phosphorylated Akt were observed only in SK-N-SH cells. Analyses of the insulin-mediated reactive oxygen species (ROS) generation and Phosphatase and Tensin homolog (PTEN) oxidation indicate that PTEN oxidation occurred in SK-N-SH cells, which can produce ROS, but not in SK-N-BE(2) cells, which cannot increase ROS in response to insulin stimulation. When SK-N-SHcells were pretreated with the NADPH oxidase inhibitor diphenyleneiodonium chloride before insulin stimulation, insulin-mediated translocation of PDK-1 to the membrane fraction and phosphorylation of Akt were remarkably reduced, whereas PI-3 kinase activity was not changed significantly. These results indicate that not only PI-3 kinase activation but also inhibition of PTEN by ROS is needed to increase cellular level of phosphatidylinositol 3,4,5-trisphosphate for recruiting downstream signaling molecules such as PDK-1 and Akt in insulin-mediated signaling. Moreover, the ROS generated by insulin stimulation mainly contributes to the inactivation of PTEN and not to the activation of PI-3 kinase in the PI-3 kinase/Akt pathway. INTRODUCTIONReactive oxygen species (ROS), and especially H 2 O 2 , are rapidly and transiently increased by a variety of external signals that include cytokines, peptide growth factors, and agonists of seven-transmembrane domain, or G proteincoupled receptors (GPCRs) (Ohba et al., 1994;Kimura et al., 1995;Krieger-Brauer and Kather, 1995;Sundaresan et al., 1995;Bae et al., 1997;Patterson et al., 1999). Previous studies have demonstrated that the binding of peptide growth factors to their specific receptors induces a transient increase in the intracellular concentration of ROS (Krieger-Brauer and Kather, 1995;Lo and Cruz, 1995;Sundaresan et al., 1996;Bae et al., 1997;Sattler et al., 1999). This growth factor-mediated transient increase of ROS is an integral constituent of downstream signal transduction (Finkel, 1998). The ROS-mediated modulation of growth factor signaling was achieved via the inactivation of PTPases through oxidation of the cysteine residue in the active site sequence motif (Zhang, 1998).ROS generation in a variety of nonphagocytic cells is much lower than in phagocytes, although the ROS generation systems in nonphagocytic cells are considered similar (Babior, 1999;Bokoch and Diebold, 2002). ROS generation in phagocytes is catalyzed by NADPH oxidase, which consists of two transmembrane subunits, p22 phox and gp91 phox , and at least three cytosolic subunits, p47 phox , p67 phox , and Rac (Babior, 1999;Banfi et al., 2003). Recently, six gp91 phox homologues (NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2) have been identified in different mammalian tissue (Banfi et al., 2003). Although the mechanism of the growth factor-mediated ROS generation in nonphagocytotic cells has not been completely understood, several recent reports (Bae et al., 200...

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“…Upon activation by EGF stimulation, Src activates the PI3-kinase/Akt pathway through both direct and indirect mechanisms (Jiang and Qiu, 2003;Kong et al, 2003;Lu et al, 2003). Activation of the PI3-kinase/Akt pathway is essential for EGF-induced cell survival and migration (Franke et al, 2003;Shien et al, 2004).…”

Section: Regulation Of Egf-induced Cell Transformation By Cbpmentioning

confidence: 99%

“…Subsequently, Src phosphorylates EGFR at several tyrosine residues that are not targeted by the receptor's autophosphorylation mechanism, including Tyr845, which is essential for EGF-induced cell proliferation (Biscardi et al, 1999). Src mediates EGF-induced activation of ERK1/2 (Mason et al, 1999;Bivona et al, 2003), and PI3K/Akt pathways (Jiang and Qiu, 2003;Kong et al, 2003;Lu et al, 2003) as well as STAT3/5, PLCg-1 and other targets (Mason et al, 1999;Olayioye et al, 1999;Bivona et al, 2003;Kong et al, 2003). The bi-directional interaction of EGFR and Src leads to a synergy in promoting cell transformation and tumorigenesis .…”

Section: Introductionmentioning

confidence: 99%

Csk-binding protein (Cbp) negatively regulates epidermal growth factor-induced cell transformation by controlling Src activation

et al. 2006

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Src Family Protein-tyrosine Kinases Alter the Function of PTEN to Regulate Phosphatidylinositol 3-Kinase/AKT Cascades

Cited by 221 publications

References 49 publications

Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes

Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes

The Major Target of the Endogenously Generated Reactive Oxygen Species in Response to Insulin Stimulation Is Phosphatase and Tensin Homolog and Not Phosphoinositide-3 Kinase (PI-3 Kinase) in the PI-3 Kinase/Akt Pathway

Csk-binding protein (Cbp) negatively regulates epidermal growth factor-induced cell transformation by controlling Src activation

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