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Enhancement of Tyrosyl Phosphorylation and Protein Expression of Eps8 by V-Src

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Enhancement of Tyrosyl Phosphorylation and Protein Expression of Eps8 by V-Src View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1450 (1999) 341^351 www.elsevier.com/locate/bba Enhancement of tyrosyl phosphorylation and protein expression of eps8 by v-Src Ming-Chei Maa a, Jun-Ru Lai b, Ruey-Wen Lin b, Tzeng-Horng Leu b;* a Institute of Biochemistry, Chung Shan Medical and Dental College, No. 113, Section 2, Ta-Ching Street, Taichung 402, Taiwan, R.O.C. b Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, 70101 Taiwan, R.O.C. Received 9 February 1999; received in revised form 28 April 1999; accepted 21 May 1999 Abstract Two eps8 isoforms, p97eps8 and p68eps8, were previously identified as substrates for receptor tyrosine kinases. Analysis of eps8 phosphotyrosine content in v-Src transformed cells (IV5) revealed that both isoforms were highly tyrosyl phosphorylated and their readiness to be phosphorylated by Src in vitro further indicated that they were putative Src substrates as well. Indeed, the enhancement of tyrosyl phosphorylation of p97eps8 detected in cells coexpressing both p97eps8 and active Src relative to that in cells expressing p97eps8 alone supported our hypothesis. The existence of common phosphotryptic peptides between in vitro 32P-labeled p97eps8 and p68eps8 indicated that these two proteins shared the same Src-mediated sites. Further in vitro binding assays demonstrated that p68eps8 was the major eps8 isoforms that could be precipitated by bacterial fusion protein containing Src SH3. Interestingly, both p68eps8 and p97eps8 were preferentially expressed in v-Src transformed cells and the presence of p68eps8 appeared to depend on Src. Since p97eps8 has been implicated in mitogenesis and tumorigenesis, its readiness to be phosphorylated and induced by v-Src might attribute to v-Src-mediated transformation. ß 1999 Elsevier Science B.V. All rights reserved. Keywords: v-Src; eps8; Tyrosyl phosphorylation; Protein expression 1. Introduction molecules, such as PLCQ, p85 subunit of PI-3 kinase, Grb2 and Shc become associated with EGFR [1]. EGF receptor (EGFR), a 170-kDa receptor tyro- Some of these proteins are further phosphorylated sine kinase, dimerizes and becomes autophosphory- by EGFR, enzymatically activated (e.g. PLCQ [2]) lated upon EGF stimulation. Through the binding and sometimes become the binding site(s) for other between pTyr and SH2, a number of SH2-containing SH2 containing protein(s) (e.g. the Grb2 binding site on Shc [3]), thereby leading to the propagation of the EGF-induced signaling. On the other hand, proteins Abbreviations: EGF, epidermal growth factor; SH2, Src ho- that devoid of SH2 domain, but still involved in mology domain 2; SH3, Src homology domain 3; pTyr, phos- EGF-induced signaling, have also been identi¢ed. A photyrosine; PLCQ, phospholipase CQ; PI-3K, phosphoinositide prominent example is eps8 [4]. 3-kinase; PH, pleckstrin homology; aa, amino acid; CE, chicken Eps8 was initially identi¢ed as a substrate for the embryo; ECL, enhanced chemiluminescence; 2D, two-dimension- al EGFR whose tyrosyl phosphorylation was increased * Corresponding author. Fax: +886-6-274-9296; in response to EGF [4]. Further studies indicated E-mail: [email protected] that eps8 could also be phosphorylated in response 0167-4889 / 99 / $ ^ see front matter ß 1999 Elsevier Science B.V. All rights reserved. PII: S0167-4889(99)00069-5 BBAMCR 14497 29-6-99 342 M.-C. Maa et al. / Biochimica et Biophysica Acta 1450 (1999) 341^351 to stimulation by various ligands including platelet- First of all, both p97eps8 and p68eps8 were highly derived growth factor and acidic ¢broblast growth tyrosyl phosphorylated in v-Src transformed cells. In factor [4]. There is a direct interaction between an immunocomplex kinase reaction, v-Src could di- EGFR and eps8 that involves the juxtamembrane rectly phosphorylate both eps8 isoforms in vitro. In- region of EGFR and the basic region of eps8, respec- terestingly, the bacterial GST fusion protein contain- tively [5]. Direct cloning of the cDNA of the EGFR ing the N-terminus of p97eps8 not only could be substrates led to the isolation of p97eps8 cDNA. And directly phosphorylated by baculovirus expressed its sequence analysis revealed the following domains Src, but also shared a common phosphotryptic pep- which might contribute to its cellular functions: an tide derived from v-Src phosphorylated p97eps8. Be- SH3 domain, a putative nuclear targeting sequence, a sides, bacterial fusion protein containing Src SH3 PH domain, several potential SH3-binding sites, and could preferentially precipitate p68eps8 in the in vitro a degenerated SH2 at the amino terminus. The eps8 binding reactions. Finally, enhanced tyrosyl phos- SH3 domain has been shown to interact with Shc [6], phorylation of p97eps8 was detected in cells coex- Shb [7], RN-tre [8], and e3B1 [9]. And interestingly, pressing both p97eps8 and active Src, but not in cells based on its deduced tertiary structure, eps8 SH3 expressing p97eps8 alone. Interestingly, in addition to domain has also been implicated in the formation tyrosyl phosphorylation, the protein levels of both of eps8 dimer [10]. Meanwhile, proteins associated eps8 isoforms were much higher in v-Src transformed with other domains of eps8 have not been identi¢ed. cells than the normal control cells. Since p97eps8 has p97eps8 has been implicated in EGF-induced mito- been implicated in mitogenesis and tumorigenesis, its genesis and tumorigenesis since its overexpression readiness to be phosphorylated and induced by v-Src in cells can enhance the EGF-dependent mitogenic may contribute to the transformation caused by v- e¡ect and focus-forming ability [4,6]. Consistent Src. with this notion was its constitutive tyrosyl phos- phorylation detected in several tumor cell lines [6]. Interestingly, in some cell lines, antibodies against 2. Materials and methods p97eps8 could also recognize a 68-kDa protein (p68eps8), which has been speculated as a proteolytic 2.1. Cloning of the murine p97eps8 full-length open or an alternatively spliced product of p97eps8 [4]. The reading frame (ORF) and the generation of its exact nature of the coding sequences and the func- expression plasmid tions of p68eps8 remain to be established. In addition to mitogenesis and tumorigenesis, the reduced ex- According to the published sequences of p97eps8 pression of both eps8 isoforms in myogenic cells sug- cDNA [4], two 18-mers P1 and P2 (nt 606^623 and gest that eps8 might also be involved in terminal nt 908^923, respectively; Fig. 1) were utilized as pri- di¡erentiation [11]. mers for polymerase chain reaction (PCR) of the Rous sarcoma virus (RSV)-encoded v-Src is the cDNA derived from mouse 11-day embryo (Clon- ¢rst identi¢ed oncoprotein with tyrosine kinase activ- tech). A PCR product with 318 nucleotides was gen- ity. Its tyrosine-speci¢c protein kinase activity is pro- erated and utilized as a probe to screen the mouse ven to be essential for cellular transformation. In 11-day embryo cDNA library. Two eps8-related v-Src transformed cells, more than 20 proteins have Vgt11 clones, 2Aa and 12Aa (Fig. 1), were isolated their pTyr contents increased and are viewed as pu- from V106 plaques and shown to be completely tative v-Src substrates [12^14]. Interestingly, some of overlapped. Both clones have been sequenced with them (i.e. cortactin, Shc, and GAP) turn out to be Sanger-dideoxy method and mapped with restriction the substrates for EGFR as well [15^20]. It was enzyme digestion. The 2Aa clone contains almost all speculated that constitutive phosphorylation of these the ORF of p97eps8 except the sequences correspond- common substrates in cells expressing v-Src might ing to the C-terminal end of eps8 (amino acid (aa) contribute to cellular transformation. In this study, 668^821). In order to make up the missing protein- we present evidence, as shown below, describing that encoding region of p97eps8, another set of oligonu- eps8 isoforms were Src substrates as well. cleotides, P3 and EcoRI-tagged P4, which corre- BBAMCR 14497 29-6-99 M.-C. Maa et al. / Biochimica et Biophysica Acta 1450 (1999) 341^351 343 The eps8 cDNA (i.e. the NaeI/HindIII digested frag- ment derived from the plasmid pBS-eps8) was ¢rst subcloned into the SmaI and HindIII sites of the Cla12Nco vector and then recloned into the ClaI site of an avian retroviral expression vector, RCAS A (BH) as described previously [22]. The pGEX-N/ RV which encodes the N-terminal p97eps8 (i.e. GST- N/RV, aa 1^179) is constructed as the following: the NaeI/EcoRV fragment derived from PBS-eps8 was ¢rst cloned into the SmaI site of pGEM-7Zf(+) and then the BamHI/EcoRI fragment derived from this new construct was ligated with the BamHI/ EcoRI-digested pGEX-2T. 2.2. Cells and cellular lysate preparation The clonal C3H10T1/2 murine ¢broblast cell lines (Neo and IV5) were generous gifts provided by Dr. Sarah J. Parsons and their derivation and mainte- nance were previously described [23,24]. Primary Fig. 1. Schematic illustration of various eps8 constructs. The chicken embryo (CE) cells were maintained and full-length eps8 cDNA is indicated on the top and its open transfected with retroviral vector as previously de- reading frame is marked as a closed box. Two Vgt11 clones, scribed [25,26]. Replication-competent RCAS A 12 Aa and 2 Aa, obtained by screening a mouse 11-day embryo (BH) and RCAS B (BH) retroviral vectors were cDN library are demonstrated. The full-length open reading eps8 frame of p97eps8 was constructed in Bluescript vector (pBS- used for the expression of p97 and active Src eps8) and RCAS (A) vector (RCAS-eps8) as described in Sec- (Src 518amb, a Src mutant with an amber mutation tion 2.
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