Src-like adaptor protein down-regulates T cell receptor (TCR)–CD3 expression by targeting TCRζ for degradation

Abstract

Src-like adaptor protein (SLAP) down-regulates expression of the T cell receptor (TCR)–CD3 complex during a specific stage of thymocyte development when the TCR repertoire is selected. Consequently, SLAP−/− thymocytes display alterations in thymocyte development. Here, we have studied the mechanism of SLAP function. We demonstrate that SLAP-deficient thymocytes have increased TCRζ chain expression as a result of a defect in TCRζ degradation. Failure to degrade TCRζ leads to an increased pool of fully assembled TCR–CD3 complexes that are capable of recycling back to the cell surface. We also provide evidence that SLAP functions in a pathway that requires the phosphorylated TCRζ chain and the Src family kinase Lck, but not ZAP-70 (ζ-associated protein of 70 kD). These studies reveal a unique mechanism by which SLAP contributes to the regulation of TCR expression during a distinct stage of thymocyte development.

Syk‐dependent regulation of Hrs phosphorylation and ubiquitination upon FcεRI engagement: Impact on Hrs membrane/cytosol localization

“…IR-mediated signals also lead to a negative-feedback regulation by the internalization and delivery of engaged receptor complexes to lysosomes for degradation [4][5][6][7][8][9][10][11].…”

Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner

“…In vivo studies have shown that SLAP deficiency leads to increased TCR expression selectively on double-positive (DP) thymocytes, where SLAP is most highly expressed (8). Previous studies have shown that the increased expression of the TCR complex on DP thymocytes is attributable to decreased intracellular retention of TCR and increased recycling (9). Increased recycling of the TCR to the cell surface leads to increased TCR levels and altered thymocyte development (8,9).…”

“…Previous studies have shown that the increased expression of the TCR complex on DP thymocytes is attributable to decreased intracellular retention of TCR and increased recycling (9). Increased recycling of the TCR to the cell surface leads to increased TCR levels and altered thymocyte development (8,9). These studies support the notion that SLAP regulates TCR levels during a specific stage of T cell development where selection events occur, and its absence leads to increased signaling through the TCR complex, thereby altering T cell development and maturation.…”

“…After washing in blocking buffer, samples again were incubated in blocking buffer, and then the secondary antibody (Alexa 555 goat anti-rabbit IgG; Molecular Probes) was added for 20 min at room temperature. Samples were washed, mounted in gel/mount (Biomeda, Foster City, CA), and visualized, and images were captured as previously described (9). BCR Recycling Assay.…”

SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2

“…It has a unique myristoylated N terminus, followed by SH3 and SH2 domains with high homology to SRC family tyrosine kinases (SFK), and a unique C terminus with binding affinity to CBL 15 . SLAP was implicated in the negative regulation of RTK 16,17 and T-cell receptor (TCR) signalling 18,19 . Owing to its homology with the SRC-SH2 domain, SLAP competes with SRC for growth factor receptor interaction and mitogenic signalling 16 while it inhibits TCR activity by docking CBL to components of the TCR complex and inducing their degradation 20 .…”