The tyrosine kinases Syk and Lyn exert opposing effects on the activation of protein kinase Akt/PKB in B lymphocytes

Li, Hsiu-Ling; Davis, William W.; Whiteman, Eileen L.; Birnbaum, Morris J.; Puré, Ellen

doi:10.1073/pnas.96.12.6890

Cited by 59 publications

(46 citation statements)

References 37 publications

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“…In the double knockout cell line, Lyn Ϫ/Ϫ Syk Ϫ/Ϫ , a slight yet reproducible increase in Akt activation was observed, possibly due to basal PI 3-kinase activity from other receptors. Our findings are in agreement with Li et al (21), and support that Akt activation in response to BCR cross-linking occurs via activation of PI 3-kinase in a pathway initiated by Syk activation.…”

Section: Syk Tyrosine Kinase Is Required For Activation Of Akt In B Csupporting

confidence: 83%

“…And second, how is activation of Akt regulated in B cells? As reported by others, Akt is activated following BCR ligation in DT40 cells, an immature B cell line, in A20 cells, a memory B cell line, and in primary B cells (21,22,38,39). The functional consequence of Akt activation in B cells, however, has not been explored.…”

Section: Discussionsupporting

confidence: 66%

“…While regulation of PI 3-kinase activity in B cells has not been well characterized, two conflicting reports indicate that the tyrosine kinases Syk and Lyn play significant roles in Akt activation in B cells (21,39). Our findings are in agreement with Li et al, who demonstrate that Syk kinase is absolutely required for BCR-induced Akt activation and that Lyn kinase plays an antagonistic role in Akt activation.…”

Section: Discussionmentioning

confidence: 99%

“…The PH domains of several signaling molecules have been demonstrated to specifically bind PIP3, resulting in the recruitment of the respective proteins to the plasma membrane. In B cells, the PH domain-containing kinases Btk and Akt (also termed protein kinase B) are activated in a PI 3-kinasedependent manner (2,21,22). While Btk is found to play a role in the sustained calcium response, a function for the serine/threonine kinase Akt in B cells has not yet been established in BCR signaling.…”

Section: T He Response Of B Lymphocytes To Foreign Ag Is Mediatedmentioning

confidence: 99%

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B Cell Antigen Receptor-Induced Activation of Akt Promotes B Cell Survival and Is Dependent on Syk Kinase

Pogue¹,

Kurosaki²,

Bolen³

et al. 2000

The Journal of Immunology

128

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Signaling through the B cell Ag receptor (BCR) is a key determinant in the regulation of B cell physiology. Depending on additional factors, such as microenvironment and developmental stage, ligation of the BCR can trigger B lymphocyte activation, proliferation, or apoptosis. The regulatory mechanisms determining B cell apoptosis and survival are not known. Using the chicken B lymphoma cell line DT40 as a model system, we investigated the role of the serine/threonine kinase Akt in B cell activation. While parental DT40 cells undergo apoptosis in response to BCR cross-linking, cells overexpressing Akt show a greatly diminished apoptotic response. By contrast, limiting the activation of Akt, either by inhibiting phosphatidylinositol 3-kinase or by ectopic expression of the phospholipid phosphatase MMAC1, results in a significant increase in the percentage of apoptotic cells after BCR cross-linking. Using various DT40 knockout cell lines, we further demonstrate that the tyrosine kinase Syk is required for Akt activation and that Lyn tyrosine kinase inhibits Akt activation. Taken together, the data demonstrate that Akt plays an important role in B cell survival and that Akt is activated in a Syk-dependent pathway.

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Section: Syk Tyrosine Kinase Is Required For Activation Of Akt In B Csupporting

confidence: 83%

Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: T He Response Of B Lymphocytes To Foreign Ag Is Mediatedmentioning

confidence: 99%

See 2 more Smart Citations

B Cell Antigen Receptor-Induced Activation of Akt Promotes B Cell Survival and Is Dependent on Syk Kinase

Pogue¹,

Kurosaki²,

Bolen³

et al. 2000

The Journal of Immunology

128

View full text Add to dashboard Cite

show abstract

“…The PI3-K are involved in a variety of cellular responses, including cell growth, survival, metabolism, di erentiation, cytoskeletal organization, and membrane tra cking (Leevers et al, 1999). Engagement of BCR has been shown to activate the activity of PI3-K (Gold and Aebersold, 1994;AagaardTillery and Jelinek, 1996;Kuwahara et al, 1996), and one of its downstream e ectors, AKT (also calledal., 1999;Li et al, 1999;Pogue et al, 2000). The role of PI3-K in regulating B cell functions was highlighted by the ®nding that mice de®cient for the regulatory p85a subunit of PI3-K demonstrated defects in B cell development and functions (Fruman et al, 1999;Suzuki et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

BCR signals target p27Kip1 and cyclin D2 via the PI3-K signalling pathway to mediate cell cycle arrest and apoptosis of WEHI 231 B cells

et al. 2001

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Cross-linking of the B cell antigen receptor (BCR) on immature WEHI 231 B cells results in G1 cell cycle arrest and apoptosis. Here we investigated the molecular mechanisms that are necessary and su cient for these changes to occur. We show that BCR stimulation of WEHI 231 cells results in down-regulation of cyclin D2 and up-regulation of p27 Kip1 , which are associated with pocket protein hypophosphorylation and E2F inactivation. Ectopic expression of p27 Kip1 by TAT-fusion protein or retroviral transduction is su cient to cause G1 cell cycle arrest, followed by apoptosis. In contrast, overexpression of cyclin D2 overcomes the cell cycle arrest and apoptosis induced by anti-IgM, indicating that downregulation of cyclin D2 is necessary for the cell cycle arrest and apoptosis activated by BCR stimulation. Thus, cyclin D2 and p27 Kip1 have opposing roles in these pathways and our data also suggest that cyclin D2 functions upstream of p27 Kip1 and the pRB pathway and therefore plays an essential part in integrating the signals from BCR with the cell cycle machinery. We next investigated which signal transduction pathways triggered by the BCR regulate cell proliferation and apoptosis via cyclin D2 and p27 Kip1 . Inhibition of PI3-K signalling by LY294002 down-regulated cyclin D2 and up-regulated p27 Kip1 expression at both protein and RNA levels, mimicking the e ects of BCR-stimulation. Furthermore, ectopic expression of a constitutively active form of AKT blocked the cell cycle arrest and apoptosis triggered by anti-IgM and also abrogated downregulation of cyclin D2 and up-regulation of p27 Kip1 expression induced by BCR-engagement. These results indicate that BCR activation targets p27 Kip1 and cyclin D2 to mediate cell cycle arrest and apoptosis and that down-regulation of PI3-K/AKT activity post BCR stimulation is necessary for these to occur. Oncogene (2001) 20, 7352 ± 7367.

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High‐grade B‐cell lymphoma developed during the treatment of chronic myeloid leukemia with bosutinib

Takakuwa

Sakai

Koh

et al. 2021

Clinical Case Reports

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Chronic myeloid leukemia (CML) accounts for approximately 15-20% of all leukemias in adults. 1 CML is characterized by the BCR-ABL1 fusion gene encoding a constitutively active tyrosine kinase. 2 Tyrosine kinase inhibitor (TKI) can help to improved the survival time in CML patients to expect almost normal life expectancy; however, the risk of secondary malignancies due to TKIs has not been completely eliminated. It is reported that second malignancies developed in 3.1-4.5%

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The tyrosine kinases Syk and Lyn exert opposing effects on the activation of protein kinase Akt/PKB in B lymphocytes

Abstract: The

Cited by 59 publications

References 37 publications

B Cell Antigen Receptor-Induced Activation of Akt Promotes B Cell Survival and Is Dependent on Syk Kinase

B Cell Antigen Receptor-Induced Activation of Akt Promotes B Cell Survival and Is Dependent on Syk Kinase

BCR signals target p27Kip1 and cyclin D2 via the PI3-K signalling pathway to mediate cell cycle arrest and apoptosis of WEHI 231 B cells

High‐grade B‐cell lymphoma developed during the treatment of chronic myeloid leukemia with bosutinib

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