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

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 con®rmed that this mutation inhibited the degradation of the M-CSF receptor. However, two di erent 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.

CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function

“…We have shown that the mutations in HDLS are unable to signal via Csf1r in the presence of CSF1 yet still express Csf1r on the surface. To confirm that loss of receptor kinase activity does not necessarily affect receptor downregulation23 we co-treated the factor dependent mutants with CSF1. In each case, addition of CSF1 down-regulated surface CSF1R (Figure 3C).…”