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Immunoglobulin µ Heavy Chains Do Not Mediate Tyrosine Phosphorylation of Ig from the ER-cis-Golgi ¹

Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University of Erlangen-Nürnberg, Erlangen, Germany

Signals delivered by Ig receptors guide the development of functional B lymphocytes. For example, clonal expansion of early µ heavy chain (µHC)-positive pre-B cells requires the assembly of a signal-competent pre-B cell receptor complex (pre-BCR) consisting of a µHC, a surrogate L chain, and the signal dimer Ig. However, only a small fraction of the pre-BCR is transported to the cell surface, suggesting that pre-BCR signaling initiates already from an intracellular compartment, e.g., the endoplasmic reticulum (ER). The finding that differentiation of pre-B cells and allelic exclusion at the IgH locus take place in surrogate L chain-deficient mice further supports the presence of a µHC-mediated intracellular signal pathway. To determine whether a signal-competent Ig complex can already be assembled in the ER, we analyzed the consequence of pervanadate on tyrosine phosphorylation of Ig in J558L plasmacytoma and 38B9 pre-B cells transfected with either a transport-competent IgL chain-pairing or an ER-retained nonpairing µHC. Flow cytometry, combined Western blot-immunoprecipitation-kinase assays, and confocal microscopy revealed that both the nonpairing and pairing µHC assembled with the Ig dimer; however, in contrast to a pairing µHC, the nonpairing µHC was retained in the ER-cis-Golgi compartment, and neither colocalized with the src kinase lyn nor induced tyrosine phosphorylation of Ig after pervanadate treatment of cells. On the basis of these findings, we propose that a signal-competent Ig complex consisting of µHC, Ig, and associated kinases is assembled in a post-ER compartment, thereby supporting the idea that a pre-BCR must be transported to the cell surface to initiate pre-BCR signaling.

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