Suppressors of T-cell receptor signaling Sts-1 and Sts-2 bind to Cbl and inhibit endocytosis of receptor tyrosine kinases.
The ubiquitin (Ub) ligase Cbl plays a critical role in attenuation of receptor tyrosine kinase (RTK) signaling by inducing ubiquitination of RTKs and promoting their sorting for endosomal degradation. Herein, we describe the identification of two novel Cbl-interacting proteins, p70 and Clip4 (recently assigned the names Sts-1 and Sts-2, respectively), that inhibit endocytosis of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor. Sts-1 and Sts-2 contain SH3 domains that interacted with Cbl, Ub-associated domains, which bound directly to mono-Ub or to the EGFR/Ub chimera as well as phosphoglycerate mutase domains that mediated oligomerization of Sts-1/2. Ligand-induced recruitment of Sts-1/Sts-2 into activated EGFR complexes led to inhibition of receptor internalization, reduction in the number of EGFR-containing endocytic vesicles, and subsequent block of receptor degradation followed by prolonged activation of mitogenic signaling pathways. On the other hand, interference with Sts-1/Sts-2 functions diminished ligand-induced receptor degradation, cell proliferation, and oncogenic transformation in cultured fibroblasts. We suggest that Sts-1 and Sts-2 represent a novel class of Ub-binding proteins that regulate RTK endocytosis and control growth factor-induced cellular functions.
Kowanetz
Katarzyna
K
Institute of Biochemistry II, Goethe University Medical School, 60590 Frankfurt, Germany.
Crosetto
Nicola
N
Haglund
Kaisa
K
Schmidt
Mirko
MHH
Heldin
Carl-Henrik
CH
Dikic
Ivan
I
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D015536:Down-Regulation; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010736:Phosphoglycerate Mutase / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D018909:src Homology Domains
C489394:CLIP4 protein, human; D002352:Carrier Proteins; D018076:DNA, Complementary; D008024:Ligands; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; C482177:Sts-2 protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; C553497:TULA-2 protein, mouse; C489397:UBASH3B protein, human; D010736:Phosphoglycerate Mutase; C067419:CBL protein, human; D013936:Thymidine