Cis and Trans Regulatory Mechanisms Control AP2-Mediated B Cell Receptor Endocytosis via Select Tyrosine-Based Motifs

Busman‐Sahay, Kathleen; Drake, Lisa A.; Sitaram, Anand; Marks, Michael S.; Drake, James R.

doi:10.1371/journal.pone.0054938

Cited by 31 publications

(48 citation statements)

References 41 publications

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“…In Igα, the sequence between the two ITAM tyrosines, DCSM, promotes AP-2 binding, while the corresponding sequence in Igβ, QTAT, blocks the binding of AP-2 (Busman-Sahay et al 2013). Consistent with these results, constructs that contain only Igα are internalized when expressed in B cells, and this occurs through the three AP-2 binding sites, which are mostly redundant (Busman-Sahay et al 2013). In contrast, constructs containing only Igβ are not internalized (Busman-Sahay et al 2013;Jang et al 2010).…”

Section: The Initiation Of Clathrin-mediated Antigen Endocytosissupporting

confidence: 69%

“…Consistent with these results, constructs that contain only Igα are internalized when expressed in B cells, and this occurs through the three AP-2 binding sites, which are mostly redundant (Busman-Sahay et al 2013). In contrast, constructs containing only Igβ are not internalized (Busman-Sahay et al 2013;Jang et al 2010). However, in the context of the full Igαβ heterodimer in the BCR as expressed by normal B cells, the membrane-proximal tyrosine of the Igβ ITAM is the most important for internalization (Busman-Sahay et al 2013;Jang et al 2010).…”

Section: The Initiation Of Clathrin-mediated Antigen Endocytosissupporting

confidence: 62%

“…Not only does mutation of this single tyrosine inhibit internalization in transfected cell lines, but mutation of both Igβ ITAM tyrosines also impairs BCR internalization in an in vivo mouse model (Gazumyan et al 2006). Furthermore, somatic mutations of the membrane-proximal ITAM tyrosine of Igβ that were identified in activated B cell-like diffuse large B cell lymphomas were associated with elevated BCR expression and decreased internalization (Busman-Sahay et al 2013;Davis et al 2010), suggesting that disturbed BCR internalization may contribute to the chronic BCR signaling that drives the growth of these tumors.…”

Section: The Initiation Of Clathrin-mediated Antigen Endocytosismentioning

confidence: 98%

“…In contrast, constructs containing only Igβ are not internalized (Busman-Sahay et al 2013;Jang et al 2010). However, in the context of the full Igαβ heterodimer in the BCR as expressed by normal B cells, the membrane-proximal tyrosine of the Igβ ITAM is the most important for internalization (Busman-Sahay et al 2013;Jang et al 2010). Not only does mutation of this single tyrosine inhibit internalization in transfected cell lines, but mutation of both Igβ ITAM tyrosines also impairs BCR internalization in an in vivo mouse model (Gazumyan et al 2006).…”

Section: The Initiation Of Clathrin-mediated Antigen Endocytosismentioning

confidence: 99%

“…Clathrin and its essential adaptor AP-2 colocalize with BCR-antigen clusters (Busman-Sahay et al 2013;Caballero et al 2006;Natkanski et al 2013;Stoddart et al 2002), and depletion of clathrin, AP-2, or the endocytic GTPase dynamin2 reduces internalization of both soluble and membrane-tethered antigens (Natkanski et al 2013;Stoddart et al 2005).…”

Section: Bcr-mediated Antigen Endocytosismentioning

confidence: 99%

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Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis

Hoogeboom

Tolar

2015

Current Topics in Microbiology and Immunology

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Generation of high-affinity, protective antibodies requires B cell receptor (BCR) signaling, as well as antigen internalization and presentation to helper T cells. B cell antigen internalization is initiated by antigen capture, either from solution or from immune synapses formed on the surface of antigen-presenting cells, and proceeds via clathrin-dependent endocytosis and intracellular routing to late endosomes. Although the components of this pathway are still being discovered, it has become clear that antigen internalization is actively regulated by BCR signaling at multiple steps and, vice versa, that localization of the BCR along the endocytic pathway modulates signaling. Accordingly, defects in BCR internalization or trafficking contribute to enhanced B cell activation in models of autoimmune diseases and in B cell lymphomas. In this review, we discuss how BCR signaling complexes regulate each of the steps of this endocytic process and why defects along this pathway manifest as hyperactive B cell responses in vivo.

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Section: The Initiation Of Clathrin-mediated Antigen Endocytosissupporting

confidence: 69%

Section: The Initiation Of Clathrin-mediated Antigen Endocytosissupporting

confidence: 62%

Section: The Initiation Of Clathrin-mediated Antigen Endocytosismentioning

confidence: 98%

Section: The Initiation Of Clathrin-mediated Antigen Endocytosismentioning

confidence: 99%

Section: Bcr-mediated Antigen Endocytosismentioning

confidence: 99%

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Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis

Hoogeboom

Tolar

2015

Current Topics in Microbiology and Immunology

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B Lymphocytes: Receptors

DeFranco

2015

Encyclopedia of Life Sciences

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B lymphocytes can synthesise Ig heavy chains that are either secreted or membrane‐bound, the latter having a transmembrane domain and a short cytoplasmic domain. Membrane‐bound Ig heavy chains and Ig light chains assemble in the ER with each other and with a heterodimer of Igα and Igβ, which mediate signalling and internalisation functions. The complex of these four polypeptides is called the B cell antigen receptor (BCR). BCR signalling occurs via three types of tyrosine kinases. Src‐family kinases phosphorylate the two tyrosine‐containing motif in the cytoplasmic domains of Igα and Igβ (the ITAMs), which recruits a second type of tyrosine kinase Syk. Syk is responsible for most downstream signalling, although calcium and diacylglycerol also require a third tyrosine kinase Btk. BCR signalling pathways are central to virtually all aspects of B cell biology, as they are required for B cell development, tolerance induction, survival and activation. Key Concepts Naïve B cells express their immunoglobulin as a cell surface receptor for antigen, called the BCR (B cell receptor for antigen). In developing precursors of B cells, the successful generation of an immunoglobulin heavy chain is sensed by the incorporation of that heavy chain into pre‐BCR molecules, which exhibit constitutive signalling. Signalling by the BCR controls development, survival and activation of B cells in a manner that is dependent on the developmental stage or activation state of the B cell. This signalling is important both for tolerisation of self‐reactive B cells and for activation of B cells recognising foreign antigen. Co‐receptors that recognise complement components, sialic acid residues, or IgG bound to antigens strongly enhance or inhibit signalling by the BCR to aid in self‐non‐self‐discrimination. The BCR is also an endocytic receptor that delivers antigen to internal compartments where protein antigens are processed into peptides and loaded onto MHC class II molecules to facilitate interactions with T cells, which are essential for production of high‐affinity antibodies. Defects in generation of BCRs or signalling components of the BCR result in B cell immunodeficiencies, the most common of which is due to loss‐of‐function mutations of the intracellular protein tyrosine kinase Btk, referred to as X‐linked agammaglobulinemia. B cell malignancies often have activated BCR signalling as a driver of their proliferation and/or survival, and selective Btk inhibitors are now approved therapeutics for some types of B cell malignancies.

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Antibody‐Drug‐Conjugate Therapy for Hematological Cancers: Matching Cell Biology with Clinical Benefit

Firer

Luboshits

2021

Adv Funct Materials

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Progress in the development and clinical efficacy of antibody-drug conjugates (ADCs) has attracted the interests of both academic researchers and the industry. The rationale for developing ADCs is based on the inherent nonselectivity of chemotherapy for tumor cells, leading to side effects that can be severe and life threatening. Another major consequence of chemotherapy is the development of drug resistance. For these reasons, targeted drug delivery (TDD) systems are being developed to specifically deliver the cytotoxic drug into the target cell. A variety of carriers that can deliver drugs to the surface or into cancer cells, one of which is the use of monoclonal antibodies, with to date ten ADCs having received FDA approval. This review will focus on the development and clinical application of five ADCs currently approved for the treatment of hematological malignancies. Following a short history that led to their regulatory approval, the review will focus on the important link between the biology of the ADC, the cell surface component targeted by the antibody component, and clinical efficacy and conclude by highlighting newer developments that strengthen this link, so that ADCs can provide long-term clinical benefit to patients with hematological cancers.

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Cis and Trans Regulatory Mechanisms Control AP2-Mediated B Cell Receptor Endocytosis via Select Tyrosine-Based Motifs

Cited by 31 publications

References 41 publications

Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis

Molecular Mechanisms of B Cell Antigen Gathering and Endocytosis

B Lymphocytes: Receptors

Antibody‐Drug‐Conjugate Therapy for Hematological Cancers: Matching Cell Biology with Clinical Benefit

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