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Cortactin, an 80/85-Kilodalton Pp60 Src Substrate, Is a Filamentous Actin-Binding Protein Enriched in the Cell Cortex Hong Wu and J

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Cortactin, an 80/85-Kilodalton Pp60 Src Substrate, Is a Filamentous Actin-Binding Protein Enriched in the Cell Cortex Hong Wu and J Cortactin, an 80/85-Kilodalton pp60 src Substrate, Is a Filamentous Actin-binding Protein Enriched in the Cell Cortex Hong Wu and J. Thomas Parsons Department of Microbiology and Cancer Center, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908 Abstract. Two relatexl cellular proteins, p80 and p85 SH3 domain had no apparent effect on the actin- (cortactin), become phosphorylated on tyrosine in binding activity. Cortactin, present in several different pp60"~-transformed cells and in cells stimulated with cell types, is enriched in cortical structures such as certain growth factors. The amino-terminal half of membrane ruffles and lamellipodia. The properties of cortactin is comprised of multiple copies of an inter- cortactin indicate that it may be important for nal, tandem 37-amino acid repeat. The carboxyl- microfilament-membrane interactions as well as trans- terminal half contains a distal SH3 domain. We report ducing signals from the cell surface to the cytoskele- that cortactin is an F-actin-binding protein. The bind- ton. We suggest the name cortactin, reflecting the cor- ing to F-actin is specific and saturable. The amino- tical subcellular localization and its actin-binding terminal repeat region appears to be both necessary activity. and sufficient to mediate actin binding, whereas the ELLS undergo structural rearrangement during cell proteins, such as filamin, villin, gelsolin , and ezrin, are division, cell migration, oncogenic transformation, enriched in the submembranous cortical region (Bretscher, C and in response to stimulation with a variety of ex- 1991). In addition, the interaction of many actin-binding tracellular ligands (Albert et al., 1989). Vertebrate cells ex- proteins with either monomeric actin or filamentous actin hibit a cortical cytoskeletal network that resides beneath, (F-actin) 1 is regulated by common intracellular signals, in- and is associated with, the inner surface of the plasma mem- eluding calcium, calmodulin, phospholipids, and protein brane (Bray et al., 1986). This cortical cytoskeleton is com- phosphorylation (Vandekerckhove, 1990; Yamashiro et al., prised of a dense network of actin filaments and associated 1990; Hartwig et al., 1992). Studies on the regulation of gel- actin-binding proteins (Small et al., 1981; Stossel et al., solin and profilin by Ca:* and phosphatidylinositides have 1981). Components of both the cell cortex and the plasma provided models for the reorganization of actin filament net- membrane are important for the integration of cell surface work (Stossel, 1989). In vivo studies have documented signals, facilitating transfer of these signals to the interior of changes in the activity of certain actin-binding proteins con- the cell. The alterations in cortical cytoskeleton accompany comitant with cellular events such as receptor stimulation a variety of cellular processes, including phagocytosis, and mitosis (Yamashiro et al., 1990; Goldschmidt-Clermont cytokinesis, cell locomotion, cell-cell and cell-substratum et al., 1991; Hartwig et al., 1992). The functional signifi- interaction, transmembrane signaling, secretion, and en- cance of actin-binding proteins is further emphasized by the docytosis (for reviews see Tilney, 1983; Albert et al., 1989; diverse phenotypes exhibited in cell lines or transgenic or- Bretscher, 1991). ganisms which either lack or overexpress actin-binding pro- The structure and physical properties of the cortical teins (for review see Noegel and Schleicher, 1991). cytoskeleton are determined, in large part, by cooperative Cellular transformation by oncogenic tyrosine kinases is and competitive interactions among many actin-binding pro- characterized by overt changes in cellular growth control and teins (Albert et al., 1989). Based on both in vitro and in vivo dramatic changes in cell morphology and cell surface topol- studies, a large number of actin-binding proteins have been ogy (for reviews see Jove and Hanafusa, 1987; Parsons and identified that control assembly and length of actin filaments, Weber, 1989). Chicken embryo (CE) cells transformed by link actin filaments into bundles or networks, define the pp60s% the oncogenic tyrosine kinase encoded by Rous three-dimensional organization of actin filaments and link sarcoma virus, are morphologically round. This phenotype filaments to other cytoplasmic and membrane components is accompanied by loss of actin stress fibers and aggregation (for reviews see Stossel et al., 1985; Pollard and Cooper, of F-actin into podosomes (David-Pfeuty and Singer, 1980; 1986; Albert et al., 1989; Stossel, 1989; Vandekerckhove, 1990; Hartwig and Kwiatkowski, 1991). Subcellular local- 1. Abbreviations used in this paper: CE, chicken embryo; F-actin, filamen- ization studies have shown that many of the actin-binding tous actin; GST, glutathione-S-transferase. The Rockefeller University Press, 0021-9525/93/03/1417/10 $2.00 The Journal of Cell Biology, Volume 120, Number 6, March 1993 1417-1426 1417 Tarone et al., 1985; Holme et al., 1986; Marchisio et al., wich, CT). CE cells were transformed by transfecting cells with plasmid 1987). The importance of the cytoskeleton in cellular trans- DNA containing the activated c-src gene, c-src527F, as described previ- ously (Reynolds et al., 1989). Both normal and transformed CE cells were formation by protein tyrosine kinase oncogenes has been maintained in DME with 5% FBS. CE cells were lysed by incubating cells supported by the study of src mutants. The transforming ac- with ice-cold G-buffer (2 mM Tris-HC1 [pH 8], 0.2 mM ATP, 0.5 mM DTT, tivity of the various pp60 s'~ mutants correlates with the de- and 0.2 mM CaCI2) for 15 rain, followed by 30 strokes with a tight-fitting gree of their association with detergent-insoluble cytoskele- Dounce homogenizer. Cell lysates were clarified by centrifugation at 10,000 g for 10 rain. The proteins were subjected to SDS-PAGE analysis, and im- ton elements (Hamaguchi and Hanafusa, 1987). The study munobiotted with either 5/~g/ml of purified anticortactin mAbs (4FI 1 or of cellular substrates of pp60 ~'~ has also pointed to the in- 1H3) or afffinity-purified rabbit phosphotyrosine antibodies, as previously volvement of cytoskeletal proteins in the process of cellular described (Wu et al., 1991). transformation and cell signaling (for reviews see Hunter, 1989; Schaller et al., 1993b). Several newly characterized F-actin Cosedimentation Assay pp60 s~ substrates are either cytoskeletal proteins or as- Rabbit muscle actin was purified as described (Pardee and Spudich, 1982). sociated with the cytoskeleton. These include FAK, a focal The purity of the actin preparation was assessed by SDS-PAGE and adhesion protein tyrosine kinase (Schaller et al., 1992); Coomassie blue staining. Typically, actin preparations were >90-95% ppl20, a tyrosine-phosphorylated protein that shares se- pure, as judged by the relative staining ofa 43-kD actin band. Purified actin quence similarity with plakoglobin and armadillo (Kanner et was stored in G-buffer. Aetin was polymerized by adjusting the buffer condi- al., 1991a; Reynolds et al., 1992); pp110, a phosphotyrosine- tion to that of F-buffer (2 mM Tris-HC1 [pH 8], 0.2 mM DTT, 0.2 mM CaCI2, 50 mM KC1, 2 mM MgCI2, and 1 mM ATP). containing protein that localizes to stress fibers in CE cells F-actin cosedimentation assays were performed by mixing either 50 t~l (Kanner et al., 1991b; Flynn, D. C., and J. T. Parsons, manu- CE cel lysate, 5-10/~1 of in vitro translation products, or 0.5-17 ttg of script in preparation); tensin, an F-actin capping and bun- glutathiune-S-transferase (GST) fusion protein with 15-30 #g of polymer- dling protein (Davis et al., 1991); p22 caveolin, a coating ized actin. The mixture (55-100 t~l) was incubated on ice for 1 h, and then layered over 50 td of 10% sucrose in F-buffer and centrifuged for 15 rain protein for nonclathrin-coated pits (Glermey and Zokas, or 1 h at 100,000 g at 4~ in a Ti42.2 rotor (Beckman Instruments, Inc., 1989; Rothberg et al., 1992); and paxillin, a focal adhesion Fullerton, CA) (Pope and Weeds, 1986; Hug et al., 1992). After removal protein associated with vinculin (Turner et al., 1990). of the supernatant, the pellet was incubated for at least 1 h with 50 td of Recently, we reported the identification of two proteins, G-buffer at 4~ and then solubilized in hot sample buffer (I.aemmli, 1970). The supernatant and pellet fractions were fractionated by SDS-FAGE, ana- designated p80/85, which are substrates for activated lyzed either by immnnoblotting with anticortactin mAbs, fluorography, or pp60 "~ protein tyrosine kinase (Wu et al., 1991). p80/85 is by Coomassie blue staining. For mAb inlubition of cortactin binding to also tyrosine phosphorylated in cells stimulated with EGF, F-actin, CE lysates were preincubated with individual anticortactin mAbs PDGF, colony stimulating factor I (Downing and Reynolds, (1-3 #g mAb/100/~g cell protein) on ice for I h before mixing the lysate 1992; Maa et al., 1992), and in platelets stimulated with with F-actin. To assess the binding of GST.pS0 fusion protein, 0.5-17/~g of purified thrombin (Wong et al., 1992; Lipfert, L., and J. S. Brugge, fusion protein was incubated with 15 t,g of polymerized actin in a total vol- personal communication), p80/85 exhibits several unique ume of 75 /~1. The cosedimentation assay was performed as described structural features. The amino-terminal half of the protein is above. The pellet was washed three times with F-hnffer before solubiliza- comprised of multiple copies of an internal, tandem tion. Supernatant and solubilized pellet fractions were fractionated by SDS- PAGE and stained with Coomassie blue. To quantitate the amount of fusion 37-amino acid repeat (referred to as "repeat region"). The protein, several different concentrations of BSA were included in the same number of repeat units appears to be specified by alternative gel to serve as internal protein concentration standards. The stained BSA splicing since, in CE cells, cDNAs have been identified that and fusion protein bands were quantitated using a Visage 4000 (Biolmage, encode proteins with five (p80) or six copies (p85) of the tan- Ann Arbor, MI) in combination with whole band analysis software.
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