title: Geldanamycin-induced Lyn dissociation from aberrant Hsp90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia.
abstract: Lyn, a tyrosine kinase belonging to the Src family, plays a key role as a switch molecule that couples the B-cell receptor to downstream signaling. In B-CLL cells, Lyn is overexpressed, anomalously present in the cytosol, and displays a high constitutive activity, compared with normal B lymphocytes. The aim of this work was to gain insights into the molecular mechanisms underlying these aberrant properties of Lyn, which have already been demonstrated to be related to defective apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Herein, Lyn is described to be in an active conformation as integral component of an aberrant cytosolic 600-kDa multiprotein complex in B-CLL cells, associated with several proteins, such as Hsp90 through its catalytic domain, and HS1 and SHP-1L through its SH3 domain. In particular, Hsp90 appears tightly bound to cytosolic Lyn (CL), thus stabilizing the aberrant complex and converting individual transient interactions into stable ones. We also demonstrate that treatment of B-CLL cells with geldanamycin, an Hsp90 inhibitor already reported to induce cell death, is capable of dissociating the CL complex in the early phases of apoptosis and thus inactivating CL itself. These data identify the CL complex as a potential target for therapy in B-CLL.
authors.affiliation: Department of Clinical and Experimental Medicine, Hematology and Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Trentin
authors.forename: Martina
authors.initials: M
authors.lastname: Frasson
authors.forename: Arianna
authors.initials: A
authors.lastname: Donella-Deana
authors.forename: Federica
authors.initials: F
authors.lastname: Frezzato
authors.forename: Mario A
authors.initials: MA
authors.lastname: Pagano
authors.forename: Elena
authors.initials: E
authors.lastname: Tibaldi
authors.forename: Cristina
authors.initials: C
authors.lastname: Gattazzo
authors.forename: Renato
authors.initials: R
authors.lastname: Zambello
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Semenzato
authors.forename: Anna M
authors.initials: AM
authors.lastname: Brunati