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McGlade Lab

Hematopoeitic signalling

Role of adaptor proteins in hematopoeitic signalling

Cellular responses to growth factor, cytokine and antigen stimulation are the consequence of signal transduction pathways mediated through tyrosine kinases. Both receptor and cytoplasmic tyrosine kinases use the assembly of multi-protein complexes to transmit, regulate and terminate these signals; deregulation of these pathways is associated with human malignancies including leukemia. Our lab studies a subset of proteins, termed adaptor proteins, which are involved in these signaling networks.

Adaptor proteins lack intrinsic enzymatic capabilities and are comprised of multiple modular domains which mediate interactions with receptor proteins, membranes, and other adaptor proteins, thereby organizing and regulating the signal transmission. Two of the adaptor proteins we are interested are the hematopoietic adaptors Gads and SLAP-2, both containing SH2 (Src-homology 2) domains and SH3 (Src-homology 3) domains.

Gads functions as a positive effector of T-cell receptor (TCR) signaling by promoting formation of a complex between two key signaling proteins SLP-76 and LAT. Gads is an adaptor protein comprised of two SH3 domains flanking one central SH2 domain. SH3 domains are most classically described as proline-recognition domains, but our lab has described a unique non-proline based interaction between a Gads SH3 domain and SLP-76. SH2 domains recognize and associate with specific tyrosine phosphorylated peptide sequences, and in the case of gads, the SH2 domain binds to phosphorylated LAT, thus bringing SLP-76 into proximity to LAT at the membrane of the cell promoting downstream TCR signaling.

On the other hand, SLAP2 appears to be a negative regulator of T-cell receptor signaling by promoting the downregulation of receptor expression on the surface of cells. It is believed that SLAP2 achieves this by promoting the degradation of receptors though association with the ubiquitin ligase c-Cbl. Interestingly, the human SLAP2 gene maps to the chromosomal region 20q, a region commonly deleted in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). We believe that loss of SLAP2, and its negative signal regulation, could contribute to the etiology of these diseases.

Our lab is currently examining the mechanistic action of Gads and SLAP2 and uncovering new roles for these two important signaling proteins.