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14-3-3? stabilizes a complex of soluble actin and intermediate filament to enable breast tumor invasion.

ABSTRACT: The protein 14-3-3? (stratifin) is frequently described as a tumor suppressor silenced in about 80% of breast tumors. Intriguingly, we show that 14-3-3? expression, which in normal breast is localized to the myoepithelial cells, tracks with malignant phenotype in two models of basal-like breast cancer progression, and in patients, it is associated with basal-like subtype and poor clinical outcome. We characterized a mechanism by which 14-3-3? guides breast tumor invasion by integrating cytoskeletal dynamics: it stabilizes a complex of solubilized actin and intermediate filaments to maintain a pool of "bioavailable" complexes for polarized assembly during migration. We show that formation of the actin/cytokeratin/14-3-3? complex and cellular migration are regulated by PKC?-dependent phosphorylation, a finding that could form the basis for intervention in aggressive breast carcinomas expressing 14-3-3?. Our data suggest that the biology of this protein is important in cellular movement and is contingent on breast cancer subtype.

SUBMITTER: Boudreau A

PROVIDER: S-EPMC3799319 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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14-3-3σ stabilizes a complex of soluble actin and intermediate filament to enable breast tumor invasion.

Boudreau Aaron A Tanner Kandice K Wang Daojing D Geyer Felipe C FC Reis-Filho Jorge S JS Bissell Mina J MJ

Proceedings of the National Academy of Sciences of the United States of America 20130925 41

The protein 14-3-3σ (stratifin) is frequently described as a tumor suppressor silenced in about 80% of breast tumors. Intriguingly, we show that 14-3-3σ expression, which in normal breast is localized to the myoepithelial cells, tracks with malignant phenotype in two models of basal-like breast cancer progression, and in patients, it is associated with basal-like subtype and poor clinical outcome. We characterized a mechanism by which 14-3-3σ guides breast tumor invasion by integrating cytoskele ...[more]

PMID: 24067649

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Project description:The phosphoserine/phosphothreonine-binding protein 14-3-3 is known to regulate actin; this function has been previously attributed to sequestration of phosphorylated cofilin. 14-3-3 was identified as an actin-associated protein in the deep-branching eukaryote Giardia lamblia; however, Giardia lacks cofilin and all other canonical actin-binding proteins (ABPs). Thus, the role of G. lamblia 14-3-3 (Gl-14-3-3) in actin regulation was unknown. Gl-14-3-3 depletion resulted in an overall disruption of actin organization characterized by ectopically distributed short actin filaments. Using phosphatase and kinase inhibitors, we demonstrated that actin phosphorylation correlated with destabilization of the actin network and increased complex formation with 14-3-3, while blocking actin phosphorylation stabilized actin filaments and attenuated complex formation. Giardia's sole Rho family GTPase, Gl-Rac, modulates Gl-14-3-3's association with actin, providing the first connection between Gl-Rac and the actin cytoskeleton in Giardia. Giardia actin (Gl-actin) contains two putative 14-3-3 binding motifs, one of which (S330) is conserved in mammalian actin. Mutation of these sites reduced, but did not completely disrupt, the association with 14-3-3. Native gels and overlay assays indicate that intermediate proteins are required to support complex formation between 14-3-3 and actin. Overall, our results support a role for 14-3-3 as a regulator of actin; however, the presence of multiple 14-3-3-actin complexes suggests a more complex regulatory relationship than might be expected for a minimalistic parasite. IMPORTANCEGiardia lacks canonical actin-binding proteins. Gl-14-3-3 was identified as an actin interactor, but the significance of this interaction was unknown. Loss of Gl-14-3-3 results in ectopic short actin filaments, indicating that Gl-14-3-3 is an important regulator of the actin cytoskeleton in Giardia. Drug studies indicate that Gl-14-3-3 complex formation is in part phospho-regulated. We demonstrate that complex formation is downstream of Giardia's sole Rho family GTPase, Gl-Rac. This result provides the first mechanistic connection between Gl-Rac and Gl-actin in Giardia. Native gels and overlay assays indicate intermediate proteins are required to support the interaction between Gl-14-3-3 and Gl-actin, suggesting that Gl-14-3-3 is regulating multiple Gl-actin complexes.

Dataset Information

14-3-3? stabilizes a complex of soluble actin and intermediate filament to enable breast tumor invasion.

Publications

14-3-3σ stabilizes a complex of soluble actin and intermediate filament to enable breast tumor invasion.

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