The Kinase PDK1 Is Essential for B-Cell Receptor Mediated Survival Signaling

Park, Sung‐Gyoo; Long, Meixiao; Kang, Jung‐Ah; Kim, Woo-Seok; Lee, Cho-Rong; Im, Sungbin; Strickland, Ian; Schulze-Luehrmann, Jan; Hayden, Matthew S.; Ghosh, Sankar

doi:10.1371/journal.pone.0055378

Cited by 19 publications

(16 citation statements)

References 33 publications

(55 reference statements)

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“…Cre mice to inactivate Pdk1, Park et al (21) recently reported that although the pre-B cell compartment was intact in these mice, PDK1 was required for the generation of immature B cells in the BM. Thus, PDK1 is necessary for pre-BCR assembly, and also appears to be necessary for the positive selection of immature B cells expressing a functional BCR.…”

Section: Discussionmentioning

confidence: 99%

PDK1 regulates B cell differentiation and homeostasis

Baracho

Cato

Zhu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Successful B cell differentiation and prevention of cell transformation depends on balanced and fine-tuned activation of cellular signaling pathways. The phosphatidyl inositol-3 kinase (PI3K) signaling pathway has emerged as a major regulator of B lymphocyte homeostasis and function. Phosphoinositide-dependent protein kinase-1 (PDK1) is the pivotal node in the PI3K pathway, regulating the stability and activity of downstream AGC kinases (including Akt, RSK, S6K, SGK, and PKC). Although the importance of PI3K activity in B cell differentiation is well documented, the role of PDK1 and other downstream effectors is underexplored. Here we used inducible and stage-specific gene targeting approaches to elucidate the role of PDK1 in early and peripheral B cell differentiation. PDK1 ablation enhanced cell cycle entry and apoptosis of IL-7-dependent pro-B cells, blocking Ig synthesis and B cell maturation. PDK1 also was essential for the survival and activation of peripheral B cells via regulation of PKC and Akt-dependent downstream effectors, such as GSK3α/β and Foxo1. We found that PDK1 deletion strongly impaired B cell receptor (BCR) signaling, but IL-4 costimulation was sufficient to restore BCR-induced proliferation. IL-4 also normalized PKCβ activation and hexokinase II expression in BCR-stimulated cells, suggesting that this signaling pathway can act independent of PDK1 to support B cell growth. In summary, our results demonstrate that PDK1 is indispensable for B cell survival, proliferation, and growth regulation.A ctivation of the phosphatidyl inositol-3 kinase (PI3K) signaling pathway is critical to early B cell development as well as peripheral B cell survival and activation (1). Although the catalytic p110 subunits of class I PI3K molecules are partially redundant, the combined loss of the p110α and p110δ isoforms results in impaired IL-7R-driven proliferation (2). Conversely, it has been suggested that attenuation of PI3K signaling via IL-7R signaling is required for pre-B cell differentiation into IgM-expressing cells to cease proliferation and promote RAG expression (3).In peripheral B cells, continued survival requires "tonic" signaling via the B cell receptor (BCR), which can be replaced by constitutive PI3K activity (4). Moreover, generation of the marginal zone (MZ) and B-1 B cell subsets, as well as antigendriven differentiation into antibody-producing cells, are dependent on PI3K (1). PI3K activity generates PtdIns(3,4,5)P 3 , which acts as a secondary messenger by binding the pleckstrin homology domains of downstream effector molecules. PtdIns (3,4,5)P 3 is also the substrate for the phosphatases PTEN and SHIP, generating PtdIns(4,5)P 2 and PtdIns(3,4)P 2 , respectively. Unrestrained activation of PI3K signaling in B cells lacking PTEN and SHIP results in lethal B cell lymphoma (5).Phosphoinositide-dependent kinase 1 (PDK1) represents a pivotal downstream effector of PI3K signaling, regulating cellular responses to growth factors, insulin, and numerous other agonists by activating a number of AGC pr...

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Section: Discussionmentioning

confidence: 99%

PDK1 regulates B cell differentiation and homeostasis

Baracho

Cato

Zhu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The phosphorylation of amino acid residue at serine 241 of PDPK1 is essential for the activation of multiple AGC family protein kinases, such as RSK2, AKT, PAK, ILK, or PKC (26,31,37). Under physiologic conditions, PDPK1 is essential for B-cell development and survival (38,39), whereas high PDPK1 activity is required for the proliferation and survival of tumor cells, including putative leukemia-initiating cells, and is also associated with disease progression and metastasis in various solid tumors and acute myeloid leukemias (40)(41)(42). However, its pathogenetic role has not been clarified in multiple myeloma.…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

et al. 2014

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Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles. Cancer Res; 74(24); 7418-29. Ó2014 AACR.

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“…Effective BCR signaling requires proper activation of NF-κB, which up-regulates the expression of the anti-apoptotic Bcl-2 family members [66, 67]. While NF-κB activation is essential for the survival of activated B cells [68, 69], exaggerated NF-κB activation and prolonged B cell survival may cause deleterious autoimmune responses [70]. Dysregulated apoptotic and anti-apoptotic genes increase B-cell lifespans and thereby promote survival of self-reactive B-cells, thus leading to autoantibodies and multiple autoimmune diseases [71, 72].…”

Section: Discussionmentioning

confidence: 99%

PKK deficiency in B cells prevents lupus development in Sle lupus mice

et al. 2017

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can result in damage to multiple organs. It is well documented that B cells play a critical role in the development of the disease. We previously showed that protein kinase C associated kinase (PKK) is required for B1 cell development as well as for the survival of recirculating mature B cells and B- lymphoma cells. Here, we investigated the role of PKK in lupus development in a lupus mouse model. We demonstrate that the conditional deletion of PKK in B cells prevents lupus development in Sle1Sle3 mice. The loss of PKK in Sle mice resulted in the amelioration of multiple classical lupus-associated phenotypes and histologic features of lupus nephritis, including marked reduction in the levels of serum autoantibodies, proteinuria, spleen size, peritoneal B-1 cell population and the number of activated CD4 T cells. In addition, the abundance of autoreactive plasma cells normally seen in Sle lupus mice was also significantly decreased in the PKK-deficient Sle mice. Sle B cells deficient in PKK display defective proliferation responses to BCR and LPS stimulation. Consistently, B cell receptor-mediated NF-κB activation, which is required for the survival of activated B cells, was impaired in the PKK-deficient B cells. Taken together, our work uncovers a critical role of PKK in lupus development and suggests that targeting the PKK-mediated pathway may represent a promising therapeutic strategy for lupus treatment.

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The Kinase PDK1 Is Essential for B-Cell Receptor Mediated Survival Signaling

Cited by 19 publications

References 33 publications

PDK1 regulates B cell differentiation and homeostasis

PDK1 regulates B cell differentiation and homeostasis

Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

PKK deficiency in B cells prevents lupus development in Sle lupus mice

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