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Bin3 encodes an evolutionarily conserved and ubiquitously expressed member of the BAR superfamily of curved membrane and GTPase-binding proteins, which includes the BAR, PCH/F-BAR, and I-BAR adapter proteins implicated in signal transduction and vesicular trafficking. In humans, Bin3 maps to chromosome 8p21.3, a region widely implicated in cancer suppression that is often deleted in non-Hodgkin's lymphomas and various epithelial tumors. Yeast studies have suggested roles for this gene in filamentous actin (F-actin) organization and cell division but its physiologic functions in mammals have not been investigated. Here we report that homozygous inactivation of Bin3 in the mouse causes cataracts and an increased susceptibility to lymphomas during aging. The cataract phenotype was marked by multiple morphologic defects in lens fibers, including the development of vacuoles in cortical fibers and a near total loss of F-actin in lens fiber cells but not epithelial cells. Through 1 year of age, no other phenotypes were apparent; however, by 18 months of age, Bin3(-/-) mice exhibited a significantly increased incidence of lymphoma. Bin3 loss did not affect normal cell proliferation, F-actin organization, or susceptibility to oncogenic transformation. In contrast, it increased the proliferation and invasive motility of cells transformed by SV40 large T antigen plus activated ras. Our findings establish functions for Bin3 in lens development and cancer suppression during aging. Further, they define Bin3 as a candidate for an unidentified tumor suppressor that exists at the human chromosome 8p21.3 locus.

Actin polymerization in cells occurs via filament elongation at the barbed end. Proteins that cap the barbed end terminate this elongation. Heterodimeric capping protein (CP) is an abundant and ubiquitous protein that caps the barbed end. We find that the mouse homolog of the adaptor protein CARMIL (mCARMIL) binds CP with high affinity and decreases its affinity for the barbed end. Addition of mCARMIL to cell extracts increases the rate and extent of Arp2/3 or spectrin-actin seed-induced polymerization. In cells, GFP-mCARMIL concentrates in lamellipodia and increases the fraction of cells with large lamellipodia. Decreasing mCARMIL levels by siRNA transfection lowers the F-actin level and slows cell migration through a mechanism that includes decreased lamellipodia protrusion. This phenotype is reversed by full-length mCARMIL but not mCARMIL lacking the domain that binds CP. Thus, mCARMIL is a key regulator of CP and has profound effects on cell behavior.