Marcus Clark, M.D.

Molecular Mechanisms by which B Cell Antigen Receptors Couple to/Activate Tyrosine Kinases

Research Summary

B-cells express a cell surface receptor (BCR) which recognizes antigen. The receptor is composed of a clonotypic antigen recognition substructure, membrane bound immunoglobulin, which is noncovalently associated with disulfide linked products of the mb-1 (Ig-alpha) and B29 (Ig alpha) genes. Depending upon the developmental stage of the cell and the context in which stimulation occurs, antigen receptor engagement can elicit a myriad of phenotypic changes including cell activation, anergy or cell death. These divergent biologic responses are triggered by a BCR initiated cascade of intracellular events.

Currently, our laboratory is pursuing three lines of investigations.

1. To identify the biochemical mechanisms by which the BCR couples to distal signaling pathways. Recently, we have demonstrated that the direct recruitment of BLNK to a specific tyrosine in Ig alpha couples the receptor to several distal signaling pathways.

2. To define the role of Ig alpha, Ig alpha and distal signaling molecules in B cell development. We are pursuing these questions using retroviral vectors to complement mice deficient in specific transcription or signaling molecules important for B cell development.
3. The molecular mechanisms of BCR intracellular trafficking. Our recent work indicates that the recruitment of specific signaling molecules insures proper sorting through the endocytic pathway and the delivery of antigen to specialized antigen processing compartments. These finding may be of importance for understanding how tolerance is maintained and autoimmunity is prevented.

Selected Papers

Wang LD, Lopes J, Cooper AB, Dang-Lawson M, Matsuuchi L, and Clark MR. Selection of B lymphocytes in the periphery is determined by the functional capacity of the B cell antigen receptor.  Proc Natl Acad Sci 101: 1027-1032, 2004.

Zhang M, Massenburg D, and Clark MR. B-cell antigen receptor signaling requirements for targeting antigen to the MHC class II presentation pathway, Curr Opin Immunology 16:382-387, 2004.

Kabak S and Clark MR. Membrane targeted peptides derived from Igα  attenuate B cell antigen receptor function.  BBRC 324:1249-1255, 2004.

Garett-Sinha LA, Hou P, Wang D, Grabiner B, Rao S, Araujo E, Yun TJ, Clark EA, Simon MC, and Clark MR.  GrpL is a target of the Ets proteins PU.1 and Spi-B involved in regulating B cell antigen receptor proximal signaling. Gene 353:134-146, 2005.

Hou P, Araujo E, Zhao T, Massenburg D, Veselits M, Doyle C, Dinner AR, and Clark MR. B cell antigen receptor signaling and internalization are mutually exclusive events. PLoS Biology e200 (Epub ahead of print). Note: Featured paper in Nature Immunology Reviews July 2006.

Cooper AB, Sawai CM, Sicinska E, Powers SE, Sincinski P, Aifantis I*, and Clark MR*. A unique role for cyclin D3 in early B cell development. Nature Immunology 7:489-497, 2006.  *co-senior and corresponding authors.

Gomez TS, McCarney SD, Labno CM, Comiskey EO, Nolz JC, Carrizosa E, Clark MR, Billadeau DD, and Burkhardt JK. A functional role for HS1 in controlling actin filament stabilization at the immunological synapse.  Immunity 24:741-752, 2006.

Araujo E and Clark MR.  Signaling pathways in T and B lymphocytes in The Autoimmune Diseases, Fourth Edition. Edited by Noel R. Rose and Ian R. Mackay. Elsevier Press, pgs: 249-260, 2006.

Zhang M, Veselits M, O'Neill S, Hou P, Reddi AL, Berlin I, Ikeda M, Nash PD, Longnecker R, Band H, and Clark MR. Ubiquitinylation of Ig-beta dictates the endocytic fate of the B cell antigen receptor.  J Immunol 179: 4435-4443.33, 2007.

Chang, A, Henderson S, Liu N, Guttikonda R, Hsieh C, Utset T, MD, Meehan S, Quigg R, Meffre E, Weigert, M, and Clark MR. In situ B cell mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. 2007, Submitted.