title: CIP4 controls CCL19-driven cell steering and chemotaxis in chronic lymphocytic leukemia.
abstract: Solid tumor dissemination relies on the reprogramming of molecular pathways controlling chemotaxis. Whether the motility of nonsolid 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 Cdc42-interacting protein 4 (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 mitogen-activated protein kinase (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.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM), U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
authors: Gema
authors: G
authors: Malet-Engra
authors: Julien
authors: J
authors: Viaud
authors: Loïc
authors: L
authors: Ysebaert
authors: Manon
authors: M
authors: Farcé
authors: Fanny
authors: F
authors: Lafouresse
authors: Guy
authors: G
authors: Laurent
authors: Frédérique
authors: F
authors: Gaits-Iacovoni
authors: Giorgio
authors: G
authors: Scita
authors: Loïc
authors: L
authors: Dupré
mesh_terms: D054415:Chemokine CCL19 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects* / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: C515460:CCL19 protein, human; D054415:Chemokine CCL19; D008869:Microtubule-Associated Proteins; D015778:Minor Histocompatibility Antigens; C406285:TRIP10 protein, human; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein