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,
*
Ludwig Institute for Cancer Research, London, United Kingdom;
Laboratory for Experimental Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands;
Laboratory for Molecular Biology, Flemish Institute for Biotechnology, Gent, Belgium;
§
The Randall Institute, Kings College, London, United Kingdom; and
¶
Department of Biochemistry and Molecular Biology, University College of London, London, United Kingdom
TNF is known to regulate macrophage (M
) migration, but the
signaling pathways mediating this response have not been established.
Here we report that stimulation of the 55-kDa TNF receptor (TNFR-1)
induced an overall decrease in filamentous actin (F-actin), inhibited
CSF-1- and Cdc42-dependent filopodium formation, and stimulated
macropinocytosis. Using a panel of TNFR-1 mutants, the regions of the
receptor required for each of these responses were mapped. The decrease
in F-actin required both the death domain and the membrane proximal
part of the receptor, whereas inhibition of filopodium formation and
increased pinocytosis were only dependent upon a functional death
domain. When the TNF-induced decrease in F-actin was inhibited using
either receptor mutants or the compound D609, TNF-stimulated actin
reorganization at the cell cortex became apparent. This activity was
dependent upon the FAN-binding region of TNFR-1. We conclude that
different domains of TNFR-1 mediate distinct changes in the M
cytoskeleton, and that the ability of TNF to inhibit M chemotaxis
may be due to decreased filopodium formation downstream of
Cdc42.
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