Solid tumor dissemination relies on the reprogramming of molecular pathways controlling chemotaxis. Whether the motility of non-solid tumors such as leukemia depends on the deregulated expression of molecules decoding chemotactic signals remains an open question. We identify here the membrane remodeling F-BAR adapter protein CIP4 as a key regulator of chemotaxis in chronic lymphocytic leukemia (CLL). CIP4 is expressed at abnormally high levels in CLL cells where it is required for CCL19-induced chemotaxis. Upon CCL19 stimulation of CLL cells, CIP4 associates with GTP-bound Cdc42 and is recruited to the rear of the lamellipodium and along microspikes radiating through the lamellipodium. Consistent with its cellular distribution, CIP4 removal impairs both the assembly of the polarized lamellipodium and directional migration along a diffusible CCL19 gradient. Furthermore, CIP4 depletion results in decreased activation of WASP, but increased activation of PAK1 and p38 MAPK. Notably, p38 MAPK inhibition results in impaired lamellipodium assembly and loss of directional migration. This suggests that CIP4 modulates both the WASP and p38 MAPK pathways to promote lamellipodium assembly and chemotaxis. Overall, our study reveals a critical role of CIP4 in mediating chemotaxis of CLL cells, by controlling the dynamics of microspike-containing protrusions and cell steering.

CIP4 controls CCL19-driven cell steering and chemotaxis in chronic lymphocytic leukemia / G. Malet-Engra, J. Viaud, L. Ysebaert, M. Farce, F. Lafouresse, G. Laurent, F. Gaits-Iacovoni, G. Scita, L. Dupre. - In: CANCER RESEARCH. - ISSN 0008-5472. - 73:11(2013 Jun 01), pp. 3412-3424.

CIP4 controls CCL19-driven cell steering and chemotaxis in chronic lymphocytic leukemia

G. Scita
Penultimo
;
2013

Abstract

Solid tumor dissemination relies on the reprogramming of molecular pathways controlling chemotaxis. Whether the motility of non-solid tumors such as leukemia depends on the deregulated expression of molecules decoding chemotactic signals remains an open question. We identify here the membrane remodeling F-BAR adapter protein CIP4 as a key regulator of chemotaxis in chronic lymphocytic leukemia (CLL). CIP4 is expressed at abnormally high levels in CLL cells where it is required for CCL19-induced chemotaxis. Upon CCL19 stimulation of CLL cells, CIP4 associates with GTP-bound Cdc42 and is recruited to the rear of the lamellipodium and along microspikes radiating through the lamellipodium. Consistent with its cellular distribution, CIP4 removal impairs both the assembly of the polarized lamellipodium and directional migration along a diffusible CCL19 gradient. Furthermore, CIP4 depletion results in decreased activation of WASP, but increased activation of PAK1 and p38 MAPK. Notably, p38 MAPK inhibition results in impaired lamellipodium assembly and loss of directional migration. This suggests that CIP4 modulates both the WASP and p38 MAPK pathways to promote lamellipodium assembly and chemotaxis. Overall, our study reveals a critical role of CIP4 in mediating chemotaxis of CLL cells, by controlling the dynamics of microspike-containing protrusions and cell steering.
Settore MED/04 - Patologia Generale
1-giu-2013
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/223954
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