Suppressor of T-cell receptor signalling 1 and 2 differentially regulate endocytosis and signalling of receptor tyrosine kinases.
Suppressor of T-cell receptor signalling 1 and 2 (Sts-1 and 2) negatively regulate the endocytosis of receptor tyrosine kinases. The UBA domain of Sts-2 and SH3-dependent Cbl-binding are required for this function. Sts-1 and -2 also possess a PGM domain, which was recently reported to exhibit tyrosine phosphatase activity. Here, we demonstrate that the PGM of Sts-1, but not of Sts-2, dephosphorylates the EGFR at multiple tyrosines thereby terminating its signalling and endocytosis. In contrast to Sts-2 the UBA of Sts-1 did not contribute significantly to receptor stabilization. Thus, although Sts-1 and Sts-2 are structurally highly homologous and both inhibit ligand-induced EGFR degradation, their mechanisms of action differ significantly. As a consequence, Sts-1-containing receptor complexes are inactive, whereas Sts-2-containing complexes are signalling competent.
Raguz
Josipa
J
Institute for Biochemistry II, Goethe University Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Wagner
Sebastian
S
Dikic
Ivan
I
Hoeller
Daniela
D
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D015536:Down-Regulation; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D066246:ErbB Receptors; D010744:Phosphoric Monoester Hydrolases