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RACK1: a Novel Substrate for the Src Protein-Tyrosine Kinase

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RACK1: a Novel Substrate for the Src Protein-Tyrosine Kinase Oncogene (2002) 21, 7619 – 7629 ª 2002 Nature Publishing Group All rights reserved 0950 – 9232/02 $25.00 www.nature.com/onc RACK1: a novel substrate for the Src protein-tyrosine kinase Betty Y Chang1, Rachel A Harte1 and Christine A Cartwright*,1 1Department of Medicine, Stanford University, Stanford, California, CA 94305, USA RACK1 is one of a group of PKC-interacting proteins endosomal membranes it may target proteins involved collectively called RACKs (Receptors for Activated C- in intracellular trafficking or transport; or if Src is Kinases). Previously, we showed that RACK1 also localized to the perinuclear membrane, it may target interacts with the Src tyrosine kinase, and is an inhibitor proteins involved in cell cycle regulation. Thus, by of Src activity and cell growth. PKC activation induces identifying distinct substrates of Src within distinct the intracellular movement and co-localization of subcellular compartments, we will learn about specific RACK1 and Src, and the tyrosine phosphorylation of functions of Src. RACK1. To determine whether RACK1 is a Src One example of a Src substrate, whose phosphoryla- substrate, we assessed phosphorylation of RACK1 by tion by Src appears to determine specific functions of various tyrosine kinases in vitro, and by kinase-active Src, is Sam68, an RNA binding protein (reviewed in and inactive mutants of Src in vivo. We found that Thomas and Brugge, 1997; Bjorge et al., 2000). Src RACK1 is a Src substrate. Moreover, Src activity is phosphorylates Sam68 during mitosis, presumably after necessary for both the tyrosine phosphorylation of breakdown of the nuclear envelope. Src appears to be RACK1 and the binding of RACK1 to Src’s SH2 important for regulating cell cycle progression via domain that occur following PKC activation. To identify Sam68, particularly during the late states of mitosis the tyrosine(s) on RACK1 that is phosphorylated by Src, and possibly during the G1/S transition. Evidence is we generated and tested a series of RACK1 mutants. We also emerging that Src may regulate gene expression at found that Src phosphorylates RACK1 on Tyr 228 and/ the post-transcriptional level via Sam68 and that Src or Tyr 246, highly-conserved tyrosines located in the can regulate mRNA splicing and/or transport sixth WD repeat that interact with Src’s SH2 domain. (reviewed in Bjorge et al., 2000). Thus, identification We think that RACK1 is an important Src substrate that and characterization of a single Src substrate has signals downstream of growth factor receptor tyrosine provided important information about the function of kinases and is involved in the regulation of Src function Src in regulating cell cycle progression and gene and cell growth. expression. Oncogene (2002) 21, 7619 – 7629. doi:10.1038/sj.onc. RACK1 (Receptor for Activated CKinase) was the 1206002 first of a group of protein kinase C (PKC)-interacting proteins that have been identified and characterized Keywords: Src; RACK1; PKC; signal transduction (reviewed in Mochly-Rosen, 1995; Mochly-Rosen and Kauvar, 1998; Schechtman and Mochly-Rosen, 2001). Using the yeast two-hybrid assay, we identified Introduction RACK1 as a novel Src-binding protein and a novel inhibitor of Src activity and cell growth (Chang et al., The Src tyrosine kinase participates in diverse signaling 1998). While a number of interacting proteins have pathways that regulate diverse cellular functions. These been identified that upregulate Src activity, few have include proliferation, differentiation, motility and been identified that downregulate Src activity. Because adhesion (reviewed in Martin, 2001; Thomas and it is the repression of c-Src activity rather than the Brugge, 1997; Abram and Courtneidge, 2000). The elevation of v-Src activity that accounts for differences subcellular localization of Src may determine, in part, is the transforming abilities of the two kinases, it is its substrate specificity and function. For example, if important to search for cellular mechanisms that Src is localized to the plasma membrane it may inactive c-Src. In doing so, we will learn about phosphorylate proteins that function in mitogenic mechanism by which normal cells regulate their signaling via growth factor receptor-tyrosine kinases, growth. or in cell adhesion, cell migration or cell – cell Previously, we found that PKC activation induces interactions. In contrast, if Src is localized to the intracellular movement and co-localization of RACK1 and Src at the plasma membrane, and the tyrosine phosphorylation of RACK1 (Chang et al., *Correspondence: CA Cartwright, CCSR Building, Room 3115-C, 2001). Together, these findings suggested that RACK1 269 Campus Drive, Stanford University School of Medicine, is a Src substrate. However, Src is only one of many Stanford, California, CA 94305-5187, USA; E-mail: [email protected] tyrosine kinases that could potentially phosphorylate Received 3 May 2002; revised 20 August 2002; accepted 29 August RACK1 in cells. The purpose of this study was to 2002 determine whether RACK1 is a Src substrate, and if RACK1: a novel substrate for the Src kinase BY Chang et al 7620 so, to identify the site(s) on RACK1 phosphorylated by Src. Using kinase active and inactive mutants of Src, we found that RACK1 is a Src substrate. Moreover, Src activity is necessary for both the tyrosine phosphorylation and the binding of RACK1 to Src’s SH2 domain that occur following PKC activation. Using mutants of RACK1 that contained phenylalanine substitutions for tyrosines, we found that Src phosphorylates RACK1 on Tyr 228 and/or Tyr 246, highly-conserved tyrosines located in the sixth WD repeat that interact with Src’s SH2 domain. Results RACK1 is an in vitro substrate for Src and not for the Abl, EGFR or PDGFR tyrosine kinases Previously, we found that RACK1 is phosphorylated on tyrosine (Chang et al., 2001). We also found that PKC activation induces the intracellular movement and co-localization of RACK1 and Src, and the tyrosine phosphorylation of RACK1. These findings suggested that Src is one tyrosine kinase that phosphorylates RACK1. To identify tyrosine kinases that phosphor- ylate RACK1 in vitro, we incubated equivalent amounts of purified GST or GST – RACK1 with purified Src (expressed from recombinant baculovirus and purified from Sf9 cells), Abl, EGFR or PDGFR Figure 1 Phosphorylation of RACK1 by Src in vitro.(a) Phos- tyrosine kinase (normalized to equivalent amounts of phorylation of GST – RACK1 by purified receptor and non-recep- tor tyrosine kinases. Purified EGFR (lanes 1 and 2), Src (lanes 3 specific activity) and performed in vitro protein-kinase and 4), Abl (lanes 5 and 6) or PDGFR (lanes 7 and 8) tyrosine assays in the presence of MnCl2, MgCl2 and kinases (normalized to equivalent amounts of specific activity) [g-32P]ATP (Figure 1a). As expected, we observed were incubated with equivalent amounts of purified GST (odd 32 autophosphorylation of all of the tyrosine kinases. In lanes) or GST – RACK1 (even lanes) and [g- P]ATP, MgCl2 and MnCl2, for 10 min at 308Cinanin vitro protein kinase assay. addition, we found that Src phosphorylated GST – 32P-labeled proteins were resolved by SDS – PAGE and visualized RACK1 (Figure 1a, lane 4) to higher stoichiometry by autoradiography. Approximate molecular masses of the ki- than did the other tyrosine kinases tested. Src also nases (kDa): EGFR, 70; c-Src, 60; c-Abl, 150; PDGFR, 180. phosphorylated GST (Figure 1a, lane 3), but at The smeared bands in lanes 5 and 6 may represents poor migra- significantly lower levels than it phosphorylated tion of the Abl kinase through the gel. RK, RACK1. (b) Phos- phorylation of GST – RACK1 by Src immunoprecipitates. GST – RACK1. To determine whether Src was phos- Proteins were immunoprecipitated with a monoclonal antibody phorylating RACK1 or the GST portion of the fusion specific for Src, MAb 327 (lanes 1 – 6 and 8 – 10) or IgG (lane protein, we proteolytically-cleaved RACK1 from 7) from NIH3T3 cell lysates expressing Y527F c-Src (lanes 1, 2 GST – RACK1 using thrombin, incubated the purified and 8), wild-type c-Src (lanes 3, 4 and 9) or vector alone (lanes 5 – 7 and 10). Immunoprecipitates of Src (lanes 1 – 6), or IgG (lane RACK1 with Src and performed an in vitro kinase 7), were incubated with equivalent amounts of purified GST (odd assay. We observed phosphorylation of the purified lanes) or GST – RACK1 (even lanes) and subjected to in vitro RACK1 by Src (data not shown). Therefore, under the protein kinase assays as described in (a), or subjected to immuno- conditions that we used, Src phosphorylates RACK1 in blot analysis with anti-Src (lanes 8 – 10) vitro, whereas the other non-receptor and receptor tyrosine kinases that we tested, do not. Interestingly, the Abl tyrosine kinase, which is evolutionarily close to tates with GST or GST – RACK1 and performed in Src in terms of catalytic-domain substrate specificity, vitro kinase assays (Figure 1b). We found that did not phosphorylate GST – RACK1 (Figure 1a, lane immunoprecipitates of Y527F Src phosphorylated 6). Previously, we showed that the Abl SH2 domain GST – RACK1 (Figure 1b, lane 2) but not GST does not binds to GST – RACK1 either (Chang et al., (Figure 1b, lane 1). A longer exposure of the 2001). autoradiogram (not shown) revealed that immunopre- To determine whether immunoprecipitates of Src cipitates of wild-type Src also phosphorylated GST – phosphorylate GST – RACK1, and whether the specific RACK1, although at significantly lower levels than did activity of Src affects its ability to phosphorylate those of Y527F Src. As expected, we observed RACK1, we immunoprecipitated similar amounts of autophosphorylation of Y527F and wild-type Src Src protein from NIH3T3 cells overexpressing Y527F (Figure 1b, lanes 1 – 4). The amount of Src present in c-Src (a partially activated and transforming c-Src each immunoprecipitate was similar (Figure 1b, lanes mutant) or wild-type c-Src, incubated immunoprecipi- 8 – 10).
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