Feedback inhibition by RALT controls signal output by the ErbB network

摘要: The ErbB-2 interacting protein receptor-associated late transducer (RALT) was previously identified as a feedback inhibitor of mitogenic signals. We now report that RALT binds to ligand-activated epidermal growth factor receptor (EGFR), ErbB-4 and ErbB-2.ErbB-3 dimers. When ectopically expressed in 32D cells reconstituted with the above ErbB tyrosine kinases (RTKs) behaved pan-ErbB inhibitor. Importantly, when tested either cell proliferation assays or biochemical experiments measuring activation ERK AKT, affected signalling activity distinct dimers different relative potencies. ΔEBR, mutant unable bind RTKs, did not inhibit ErbB-dependent consistent exerting its suppressive towards these pathways at receptor-proximal level. Remarkably, ΔEBR retained ability suppress largely proliferative over wide range ligand concentrations, indicating can intercept signals also receptor-distal A function EGFR detected low levels occupancy, but completely overcome by saturating concentrations ligand. propose quantitative qualitative aspects concur defining identity, strength duration generated network.