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

Siemasko K, Eisfelder BJ, Brown B, Stebbins C, Kabak S, Sant A, Song W, Clark MR. (1999). Ig alpha and Ig beta are required for efficient trafficking to late endosomes and to enhance antigen presentation. J. Immunol.162: 6518-6525.

Garrett-Sinha LA, Su GH, Rao S, Kabak S, Hao Z, Clark MR, Simon MC. (1999). PU.1 and Spi-B are required for normal B cell (BCR)-mediated signal transduction. Immunity 10(4):399-408.

Siemasko K and Clark MR. (2001). Regulation of MHC-class II-restricted antigen processing. Curr. Opin. Immunol. 13:32-36.

Hu C-J, Rao S, Ramirez-Bergeron D.L., Garrett-Sinha LA, Gerondakis S, Clark MR and Simon MC. (2001). PU.1 and Spi-B regulate c-rel. Immunity. 15:545-555.

Siemasko K, Skaggs B, Kabak S, West Williamson E, Brown B, Song W and Clark MR. (2002). B cell antigen receptor trafficking to MIIC proceeds through sequential Ig alpha dependent targeting and fusion checkpoints. J. Immunol. 168:2127-2138.

Sun T, Clark MR, and Storb U. (2002). A point mutation in the constant region of Ig lambda1 prevents normal B cell development due to defective BCR signaling. Immunity 16(2):245-257.

Kabak S, Skaggs B, Gold MR, Affolter M, West K, Foster M, Siemasko K, Chan AC, Aebersold R and Clark MR. (2002). The direct recruitment of BLNK to Ig alpha couples the BCR to distal signaling pathways. Mol. Cell. Biol. 22(8):2524-2535.

Li C, Siemasko K, Clark MR and Song W. (2002). Efficiency of antigen processing is dependent on the kinetics and specificity of antigen. Int. Immunology 14:1179-1191.

Wang, LD and Clark, MR. (2003). B-cell antigen-receptor signalling in lymphocyte development. Immunology110:411-420.

Wang, LD, Lopez J. Cooper AB, Dang-Lawson M, Matsuuchi L and Clark MR. (2004). Selection of B lyphocytes in the periphery is determined by the funtional capacity of the B cell antigen recptor. Proc. Natl. Acad. Sci. 101:1027-1032.

Clark, MR, Massenburg, D., Siemasko, K, Hou, P., Zhang, M. (2004). B-cell antigen receptor signaling requirements for targeting antigen to the MHC class II presentation pathway. Curr Opin Immunol 16:382-387.

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

Skaggs BJ and Clark MR. (2004). Proximal B cell receptor signaling pathways: A review. Signal Transduction 5:173-194