INTERNALIZATION OF THE INTERLEUKIN-6 SIGNAL TRANSDUCER GP130 DOES NOTREQUIRE ACTIVATION OF THE JAK STAT PATHWAY/

Signalling receptors often undergo receptor-mediated endocytosis. In m any cases this internalization is stimulated by ligand binding and act ivation of intrinsic receptor tyrosine kinases, resulting in a recepto r down-regulation. We have analysed whether internalization of the int erleukin 6 signal transducer gp130 is dependent on the activation of r eceptor-associated Jak kinases. By using a chimaeric receptor system w e found that receptor mutants that lack box1 and therefore are not cap able of activating Jak and signal transducer and activator of transcri ption (STAT) proteins are still endocytosed efficiently. A chimaeric r eceptor with the recently identified dileucine internalization motif b eing replaced by two alanine residues was not efficiently internalized but still capable of recruiting STATs. Furthermore an antagonistic an tibody that inhibits the signalling of all interleukin-6-type cytokine s via gp130 was internalized as efficiently as an agonistic one that a ctivates the Jak/STAT pathway. Our findings suggest that the endocytos is of gp130 is signal-independent.