Biomedical subjects

Shara Kabak

Publications and source records attributed to Shara Kabak.

3 recordsLinked to original sources

PubMed2004

Membrane-targeted peptides derived from Igalpha attenuate B-cell antigen receptor function.

Within the B-cell antigen receptor (BCR), heterodimers of Igalpha/Igbeta couple the receptor to intracellular signaling pathways. In the resting state, Igalpha associates with Src-family tyrosine kinases (SFTKs) which contain some basal activity. Upon engagement of the receptor, the SFTKs phosphorylate tyrosine residues in the BCR that recruit and activate the tyrosine kinase Syk, initiating signaling pathways. To test the hypothesis that disrupting the association between the resting receptor and the SFTKs would attenuate both basal and induced receptor activities, we expressed non-phosphorylatable membrane-targeted analogs of Igalpha (Igalpha/M) or Igbeta (Igbeta/M) in B lymphocytes. Both Igalpha/M and Igbeta/M inhibited BCR-induced calcium mobilization, but only Igalpha/M was able to diminish tyrosine phosphorylation. In an immature B-cell line, Igalpha/M attenuated both receptor-induced and basal apoptosis. Taken together, these data demonstrate the importance of the resting receptor complex and suggest therapeutic strategies for regulating receptor-mediated functions.

Antigens, CD↗

PubMed2002

Receptor-facilitated antigen presentation requires the recruitment of B cell linker protein to Igalpha.

Ags that cross-link the B cell Ag receptor are preferentially and rapidly delivered to the MHC class II-enriched compartment for processing into peptides and subsequent loading onto MHC class II. Proper sorting of Ag/receptor complexes requires the recruitment of Syk to the phosphorylated immunoreceptor tyrosine-based activation motif tyrosines of the B cell Ag receptor constituent Igalpha. We postulated that the Igalpha nonimmunoreceptor tyrosine-based activation motif tyrosines, Y(176) and Y(204), contributed to receptor trafficking. Igalpha(YDeltaF(176,204))/Igbeta receptors were targeted to late endosomes, but were excluded from the vesicle lumen and could not facilitate the presentation of Ag to T cells. Subsequent analysis demonstrated that phosphorylation of Y(176)/Y(204) recruited the B cell linker protein, Vav, and Grb2. Reconstitution of Igalpha(YDeltaF(176,204))/Igbeta with the B cell linker protein rescued both receptor-facilitated Ag presentation and entry into the MHC class II-enriched compartment. Thus, aggregation accelerates receptor trafficking by recruiting two separate signaling modules required for transit through sequential checkpoints.

Adaptor Proteins, Signal Transducing↗

PubMed2002

The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways.

Following B-cell antigen receptor (BCR) ligation, the cytoplasmic domains of immunoglobulin alpha (Ig alpha) and Ig beta recruit Syk to initiate signaling cascades. The coupling of Syk to several distal substrates requires linker protein BLNK. However, the mechanism by which BLNK is recruited to the BCR is unknown. Using chimeric receptors with wild-type and mutant Ig alpha cytoplasmic tails we show that the non-immunoreceptor tyrosine-based activation motif (ITAM) tyrosines, Y176 and Y204, are required to activate BLNK-dependent pathways. Subsequent analysis demonstrated that BLNK bound directly to phospho-Y204 and that fusing BLNK to mutated Ig alpha reconstituted downstream signaling events. Moreover, ligation of the endogenous BCR induced Y204 phosphorylation and BLNK recruitment. These data demonstrate that the non-ITAM tyrosines of Ig alpha couple Syk activation to BLNK-dependent pathways.

Adaptor Proteins, Signal Transducing↗