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Evidence that downregulation of the M-CSF receptor is not dependent upon receptor kinase activity

Oncogene volume 18, pages 3846–3851 (1999)Cite this article

Abstract

The downregulation of tyrosine kinase receptors attenuates signalling and is thought to be dependent upon intrinsic receptor kinase activity, largely because downregulation is inhibited by a kinase-inactivating mutation of an invariant lysine residue of the receptors for EGF, insulin, M-CSF and PDGF. We confirmed that this mutation inhibited the degradation of the M-CSF receptor. However, two different kinase inactivating mutations of the invariant amino acids Gly 591 and Glu 633 did not prevent M-CSF-induced receptor degradation, so demonstrating that receptor kinase activity is not essential for this process. Three other kinase-inactivating mutations were found to cause constitutive receptor degradation in the absence of M-CSF, most probably by disrupting the structure of the activating loop of the kinase domain. It is known that extensive movement of the A-loop is necessary for kinase activation and is normally induced by ligand-binding. It is therefore suggested that some aspect or consequence of the change in structure of the A-loop caused by ligand binding also activates receptor downregulation, so ensuring that downregulation is coupled to but is not necessarily dependent upon receptor kinase activity.

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Acknowledgements

We are particularly grateful for the help and encouragement of John White and would also like to thank Chiron for the M-CSF and Steve Dilworth, Bill Gullick, Jenna Hutton and Louise Johnson for their helpful comments. This work was funded in part by the BBSRC. MU and GM were recipients of PhD studentships from the Cancer Research Campaign and Medical Research Council. Correspondence and request for materials should be addressed to ND (ndibb@rpms.ac.uk).

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  1. M Uden and G M Morley: M Uden and G Morley made equal contributions.

Authors and Affiliations

  1. Division of Paediatrics, Cell Signalling Unit, Obstetrics and Gynaecology, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 ONN, UK

    M Uden, G M Morley & N J Dibb

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Uden, M., Morley, G. & Dibb, N. Evidence that downregulation of the M-CSF receptor is not dependent upon receptor kinase activity. Oncogene 18, 3846–3851 (1999). https://doi.org/10.1038/sj.onc.1202743

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