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J Biol Chem, Vol. 274, Issue 45, 31863-31867, November 5, 1999

Kaposi's Sarcoma-associated Herpesvirus-encoded G Protein-coupled Receptor Activation of c-Jun Amino-terminal Kinase/Stress-activated Protein Kinase and Lyn Kinase Is Mediated by Related Adhesion Focal Tyrosine Kinase/Proline-rich Tyrosine Kinase 2^*

Neru Munshi^§, Ramesh K. Ganju^§, Shalom Avraham, Enrique A. Mesri^¶, and Jerome E. Groopman

From the  Division of Experimental Medicine and Hematology/Oncology, Robert Mapplethorpe Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115 and the ^¶ Laboratory of Viral Oncogenesis, Division of Hematology-Oncology, Cornell University Medical College, New York, New York 10021

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

The Kaposi's sarcoma-associated herpesvirus (KSHV) (also known as human herpesvirus 8) has been implicated in the pathogenesis of Kaposi's sarcoma and B cell primary effusion lymphomas. KSHV encodes a G protein-coupled receptor (GPCR) that acts as an oncogene and constitutively activates two protein kinases, c-Jun amino-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and p38 mitogen-activated protein kinase. It also induces the production of vascular endothelial growth factor. These processes are believed to be important in KSHV-GPCR-related oncogenesis. We have characterized the signaling pathways mediated by KSHV-GPCR in a reconstituted 293T cell model in which the related adhesion focal tyrosine kinase (RAFTK) was ectopically expressed. RAFTK has been shown to play an important role in growth factor signaling in endothelium and in B cell antigen receptor signaling in B lymphocytes. KSHV-GPCR induced the tyrosine phosphorylation of RAFTK. Expression of wild-type RAFTK enhanced GPCR-mediated JNK/SAPK activation, whereas dominant-negative mutant constructs of RAFTK, such as K457A (which lacks kinase activity) and Y402F (a Src-binding mutant), inhibited KSHV-GPCR-mediated activation of JNK/SAPK. RAFTK also mediated the KSHV-GPCR-induced activation of Lyn, a Src family kinase. However, RAFTK did not mediate the activation of p38 mitogen-activated protein kinase induced by KSHV-GPCR. Human interferon -inducible protein-10, which is known to inhibit KSHV-GPCR activity, was found to reduce RAFTK phosphorylation and JNK/SAPK activation. These results suggest that in cells expressing RAFTK/proline-rich tyrosine kinase 2, such as endothelial and B cells, RAFTK can act to enhance KSHV-GPCR-mediated downstream signaling to transcriptional regulators such as JNK/SAPK.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

The pathogenesis of Kaposi's sarcoma (KS),¹ which is the major neoplastic manifestation of AIDS, has been the focus of considerable interest (1-4). Prior data have supported a cytokine-driven proliferation of the tumor spindle cells (5-7). Recently, KS-associated herpesvirus (KSHV), also known as human herpesvirus 8, was shown to be consistently present in lesions of both AIDS-related and non-AIDS-associated KS, as well as in certain B cell primary effusion lymphomas (8-12). This virus is believed to play an important role in the development of these neoplasms. KSHV has been shown to induce transformation of endothelial cells. These cells show an up-regulation of the vascular endothelial growth factor receptor, Flk-1/KDR and are dependent on vascular endothelial growth factor production (13).

KSHV contains a number of open reading frames that encode known cellular homologues of various proteins, including cytokines and cell cycle and apoptotic regulatory proteins, as well as chemokines and their receptors (14-20). One of these KSHV-encoded genes, open reading frame 74, has been named KSHV G protein-coupled receptor (GPCR) because it shows homology to several -chemokine receptors, including CXCR1, CXCR2, and CXCR3 (21-24). KSHV-GPCR binds a number of CXC chemokines, including interleukin-8, growth-related oncogene-, IFN--inducible protein-10 (IP-10), and stromal cell-derived factor 1 (24, 25). Some of these CXC chemokines, such as GRO peptides, have been shown to act as potent agonists in stimulating KSHV-GPCR signaling (25, 26), whereas IP-10 and stromal cell-derived factor 1 have been shown to down-modulate KSHV-GPCR (25-28). Transfer of the KSHV-GPCR gene into model cell lines has resulted in a number of cellular responses, including cell proliferation, transformation, and production of vascular endothelial growth factor (21, 22).

Despite increasing knowledge about the prominent role of KSHV-GPCR in the pathogenesis of KS, relatively little is known about the signal transduction pathways downstream of this receptor. KSHV-GPCR has been shown to constitutively activate two transcriptional mediators, JNK/SAPK and p38/MAPK (21, 22), although intermediate steps from the surface receptors to these mediators are uncharacterized.

RAFTK, also known as proline-rich tyrosine kinase 2 (Pyk2), CAK-, and CADTK, exhibits about 45% amino acid identity with the focal adhesion kinase (29-31) and has been shown to be activated by vascular endothelial growth factor and other cytokines in KS and in untransformed endothelial cells (32, 33). RAFTK is also involved in the signaling pathways induced by T and B cell antigen receptors, integrins, and G protein-coupled receptors (34-37).

In the present study, we have addressed whether RAFTK participates in KSHV-GPCR-induced JNK/SAPK and p38 MAPK activation. We observed that KSHV-GPCR induced RAFTK activation, which enhanced KSHV-GPCR-induced JNK/SAPK activation. However, RAFTK activation did not lead to p38 MAPK activation. Furthermore, the Src-related kinase, Lyn, was also involved in KSHV-GPCR signaling. Our results suggest that KSHV-GPCR can activate a variety of downstream substrates that lead to activation of JNK/SAPK family members, thereby mimicking pathways of exogenous cytokine stimulation in KS cells.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Reagents and Antibodies-- RAFTK antibodies were obtained as described previously (36). Antibodies to Lyn, JNK, p38, and recombinant glutathione S-transferase-c-Jun amino-terminal protein (1-79 amino acids) (GST c-Jun 1-79) were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-phosphotyrosine monoclonal antibody (4G10) was a generous gift from Dr. Brian Druker (Oregon University, Portland, OR). Electrophoresis reagents were obtained from Bio-Rad Laboratories. The protease inhibitors and all other reagents were obtained from Sigma. The nitrocellulose membrane was obtained from Bio-Rad. The chemokine, human IP-10, was obtained from Peprotech Inc. (Rocky Hill, NJ).

Cell Culture-- 293T cells, known to lack RAFTK, were used for the present studies. These cells were grown in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum and antibiotics. Cells were grown to confluence in 100-mm tissue culture dishes and were fed with fresh medium 3 h prior to transfection.

Transient Transfections-- KSHV-GPCR was cloned into the expression vector pCEFL, as described (22), to obtain pCEFL-KSHV-GPCR. Parent pCEFL vector was used as a control. Wild-type RAFTK (RAFTK^WT), kinase-dead mutant RAFTK (RAFTK^m457), or Src-binding mutant RAFTK (RAFTK^m402) was subcloned into a pCDNA expression vector. The dominant-negative kinase mutant RAFTK^m457 was generated by replacing Lys-457 with Ala, and RAFTK^m402 was obtained by replacing Tyr-402 with Phe by site-directed mutagenesis. Controls consisted of pCDNA vector alone. GST-JNK and GST p38 MAPK were also cloned into pCDNA expression vectors. 293T cells were grown in 100-mm dishes, and transfections with these various vectors were carried out by the calcium phosphate method (Life Technologies, Inc.) according to the manufacturer's recommendations. Briefly, after 16 h of incubation at 37 °C with transfection medium containing different expression vectors, the medium was replaced and the cells were incubated for another 24-36 h. Total cell lysates were analyzed for expression of proteins by blotting with anti-RAFTK or GST antibodies.

IP-10 Treatment-- 293T cells transiently transfected with KSHV-GPCR, RAFTK^WT, and GST-JNK were treated with 100 ng/ml IP-10 for various time periods. The cells were lysed within the culture dish by adding modified radioimmune precipitation buffer as described below.

Immunoprecipitations and Western Blotting-- Immunoprecipitations were carried out as described (34). Briefly, the cells were washed and lysed with modified radioimmune precipitation buffer (50 mM Tris-HCl, pH 7.4, 1% Nonidet P-40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml each of aprotinin, leupeptin, and pepstatin, 10 mM sodium vanadate, 10 mM sodium fluoride, and 10 mM sodium pyrophosphate). For the immunoprecipitation studies, identical amounts of protein from the total cell lysates of each sample were first clarified by incubation with 50 µl of 10% protein A-Sepharose solution (Amersham Pharmacia Biotech) for 1 h at 4 °C. The protein A-Sepharose beads were then removed by brief centrifugation, and the supernatants were incubated with different primary antibodies for 1 h at 4 °C followed by the addition of 50 µl of protein A-Sepharose and further incubation for 16 h at 4 °C. Nonspecific proteins were removed by washing the Sepharose beads three times with the lysis buffer and once with phosphate-buffered saline. Bound proteins were solubilized in 40 µl of 2× Laemmli buffer and further analyzed by immunoblotting. Samples were separated by SDS-PAGE (8% polyacrylamide) and then transferred to nitrocellulose membranes. The membranes were blocked with 5% nonfat milk protein and probed with primary antibody for 2 h at room temperature or overnight at 4 °C. Immunoreactive bands were visualized by using horseradish peroxidase-conjugated secondary antibody and the enhanced chemiluminescence system (Amersham Pharmacia Biotech).

JNK/SAPK and p38 MAPK Assays-- Total cell lysates were immunoprecipitated with JNK/SAPK or p38 kinase antibodies. The immune complexes were washed twice with radioimmune precipitation buffer and twice with kinase buffer (50 mM HEPES, pH 7.4, 10 mM MgCl₂, 20 µM ATP). The complexes were then incubated for 30 min at room temperature with 5 µCi of [-³²P]ATP and with the substrates GST-c-Jun (1-79) (1 µg) for JNK or myelin basic protein (7 µg) for p38 MAPK. The reaction was stopped by adding 2× SDS sample buffer and boiling the samples for 5 min at 100 °C. The reaction products were resolved by 15% SDS-PAGE and detected by autoradiography.

Lyn Kinase Assay-- A Src-related Lyn kinase assay was performed as described (38). Briefly, the complexes obtained by immunoprecipitating cell lysates with Lyn antiserum were washed twice with lysis buffer and once with kinase buffer (10 mM HEPES, pH 7.4, 5 mM MnCl₂, 10 µM Na₃VO₄). For the in vitro kinase assays, the immune complex was incubated for 30 min at room temperature in kinase buffer containing acid-denatured rabbit muscle enolase (Sigma) and 5 µCi of [-³²P]ATP. The reaction was stopped by adding 2× SDS sample buffer and boiling the samples for 5 min. The samples were then subjected to SDS-PAGE and detected by autoradiography.

RAFTK Kinase Assay-- The RAFTK kinase assay was performed as described (36). Briefly, RAFTK immunoprecipitates were washed twice with radioimmune precipitation buffer and once in kinase buffer (20 mM HEPES, pH 7.4, 50 mM NaCl, 5 mM MgCl₂, 100 mM Na₃VO₄, and 5 µM ATP). The immunocomplexes were incubated in kinase buffer containing 25 µg of poly(Glu/Tyr) (4:1, 20-50 kDa, Sigma) and 5 µCi of [-³²P]ATP for 30 min at room temperature.

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Accruing information indicates that KSHV is involved in the pathogenesis of KS and certain B cell malignancies (11, 39, 40). KSHV-encoded G protein-coupled receptor can transform NIH3T3 cells. Recently, it was demonstrated that KSHV-GPCR activated both JNK/SAPK and p38 MAPK in a 293T cell model (22). We have extended these initial observations and characterized intermediate signaling molecules present in endothelium and B lymphocytes that may link KSHV-GPCR to transcriptional activation.

We focused on the effects of KSHV-GPCR on RAFTK. RAFTK has been shown to act as a bridge by directing cytokine, chemokine, or stress-activated signaling downstream to the nuclear activating proteins of the AP-1 family via JNK/SAPK activation and to cytoskeletal elements such as paxillin (34-37, 41-43). Our model system employed 293T cells, which lack native RAFTK. Co-transfection of KSHV-GPCR with different RAFTK constructs allowed us to assess how RAFTK might participate in KSHV-GPCR-mediated signaling pathways.

As shown in Fig. 1, higher RAFTK phosphorylation was observed in 293T cells co-expressing KSHV-GPCR and RAFTK^WT as compared with cells expressing both the control vector (pCEFL) and RAFTK^WT. Furthermore, KSHV-GPCR did not induce phosphorylation in the RAFTK^m457 mutant that lacks kinase activity. Equal amounts of RAFTK protein were expressed in each transfectant, as shown in the bottom panel of Fig. 1. We also found that KSHV-GPCR enhanced RAFTK auto-kinase activity (data not shown). These studies indicate that KSHV-GPCR activates RAFTK and could therefore signal via this kinase.

View larger version (38K): [in this window] [in a new window]   Fig. 1.   KSHV-GPCR induces phosphorylation of RAFTK in a reconstituted 293T cell model. 293T cells were transiently transfected by the calcium phosphate method with KSHV-GPCR (10 µg in each plate) and RAFTKWT (2 µg per plate) or with RAFTKm457 (2 µg per plate). The cells transfected with the pCEFL vector (10 µg in each plate) and RAFTKWT or RAFTKm457 were used as controls. The transfected lysates were immunoprecipitated with anti-RAFTK antibody. Immunoprecipitates were size-fractionated by 7.5% SDS-PAGE, transferred onto a nitrocellulose membrane, and then serially blotted with anti-phosphotyrosine (top panel) and anti-RAFTK antibodies (bottom panel). Control lane represents immunoprecipitation with the control antibody. GPCR, KSHV-GPCR; MW, molecular weight (in thousands).

KSHV-GPCR is known to constitutively activate JNK/SAPK (22). Because RAFTK/Pyk2 is known to regulate JNK activation in chemokine and stress-induced signaling (41, 43), we decided to investigate whether RAFTK can modulate JNK activation by KSHV-GPCR. As shown in Fig. 2, there was an approximately 4-fold increase in JNK activity in the presence of KSHV-GPCR. However, expression of RAFTK^WT led to an approximately 9-fold increase in this activity. Equivalent transfection efficiencies were shown by immunoprecipitating with glutathione-Sepharose beads and then blotting with anti-GST antibody (Fig. 2A, bottom panel). The JNK activation was found to be dependent on the level of RAFTK expressed in these cells (Fig. 3).

View larger version (21K): [in this window] [in a new window]   Fig. 2.   Co-expression of RAFTK enhances KSHV-GPCR-induced JNK/SAPK activation. 293T cells were transfected with KSHV-GPCR (10 µg) and GST-JNK (1 µg per plate) and the RAFTK constructs RAFTKWT (2 µg per plate), RAFTKm457, or RAFTKm402 or pCDNA (2 µg per plate), as shown. pCEFL vector (10 µg per plate) was used as a control. A, top panel, the respective lysates were assayed for JNK activity as described under "Experimental Procedures." Bottom panel, the transfected lysates were size-fractionated and then blotted with -GST antibody. B, fold activation of JNK activity.

View larger version (22K): [in this window] [in a new window]   Fig. 3.   RAFTK activates KSHV-GPCR-induced JNK activity in a dose dependent manner. 293T cells were transfected with KSHV-GPCR (10 µg), GST-JNK (1 µg), and varying concentrations of RAFTK, and the cell lysates were assayed for JNK activity. MW, molecular weight (in thousands).

To test whether the kinase activity of RAFTK/Pyk2 was required for enhancement of KSHV-GPCR-induced JNK/SAPK activity, we used a catalytically inactive mutant of RAFTK (RAFTK^m457). As shown in Fig. 2A, expression of RAFTK^m457 did not enhance KSHV-GPCR-mediated JNK/SAPK activation, suggesting that the kinase activity of RAFTK is required for JNK activation. Prior analyses of RAFTK indicate that the SH2 domain of Src binds to the Tyr-402 residue, which is the autophosphorylation site of RAFTK/Pyk2. This binding leads to the activation of Src and other downstream signaling molecules. In the present studies, we observed that expression of RAFTK^m402 failed to mediate KSHV-GPCR-induced JNK activation. Taken together, these studies indicate that RAFTK enhances KSHV-GPCR-induced JNK activation, and this effect is dependent on RAFTK autophosphorylation and kinase activity.

p38 MAPK, another member of the mammalian MAPK family, is also known to be activated by KSHV-GPCR (22). p38 MAPK participates in signaling pathways that regulate the activation and phosphorylation of transcriptional factors, including CHOP, Elk-1, and ATF-2 (44-46). Because it has been shown that RAFTK can mediate activation of p38 MAPKs induced by DNA damaging agents (47), we therefore investigated whether RAFTK also functioned as an intermediate signaling molecule in the KSHV-GPCR pathway leading to p38 MAPK. We did not observe increased p38 MAPK activity in the presence of RAFTK^WT as compared with pCDNA control (Fig. 4). This result indicates that there are distinct downstream pathways mediating GPCR effects on these two transcriptional activators.

View larger version (35K): [in this window] [in a new window]   Fig. 4.   p38 activation by KSHV-GPCR is not mediated by RAFTK. 293T cells were transfected with KSHV-GPCR (10 µg), GST-p38 (1 µg), and either RAFTKWT (2 µg) or pCDNA (2 µg). pCEFL (10 µg) was used as a vector control. The lysates were immunoprecipitated and assayed for p38 MAPK as described under "Experimental Procedures." MW, molecular weight (in thousands); MBP, myelin basic protein.

RAFTK has been shown to act as a "platform kinase" and interacts with several signaling molecules, including Src-related kinases and adaptor proteins in various cell types (34-37). Association of RAFTK with the Src-related kinase Fyn plays an important role in mediating T cell receptor signal transduction (34, 48). We therefore investigated the role of Src kinases in GPCR-induced signaling. 293T cells were characterized by Western blotting and immunoprecipitation for the expression of Src family kinases and were found to express significant amounts of Lyn. As shown in Fig. 5, RAFTK^WT enhanced Lyn activity using enolase as substrate in the presence of KSHV-GPCR, whereas RAFTK^m457 and RAFTK^m402 had no such effect. This suggests that RAFTK could mediate the activation of Src kinases by KSHV-GPCR. The Src-related kinase 1, Syk, has recently been shown to play an important role in the activation of KSHV gene product (K1) signaling (19).

View larger version (35K): [in this window] [in a new window]   Fig. 5.   RAFTK mediates KSHV-GPCR-induced Lyn kinase activity. 293T cells were transfected with the various constructs shown, at the concentrations as described in Fig. 2. Lysates from the transfected cells were immunoprecipitated with anti-Lyn antibody. The immune complexes were subjected to an in vitro kinase assay with enolase as the substrate. The 32P-incorporated proteins were resolved by SDS-PAGE (7.5% polyacrylamide), followed by autoradiography. Control lane represents the immunoprecipitates with the control antibody. MW, molecular weight (in thousands).

KSHV-GPCR shows homology to several CXC chemokine receptors, including the IP-10 receptor CXCR3. IP-10 has been shown to inhibit KSHV-GPCR-induced constitutive signaling (25-27). We observed a reduction of about 80% in the tyrosine phosphorylation of RAFTK upon IP-10 treatment (Fig. 6A, top panel). Equivalent amounts of RAFTK were present in each sample (Fig. 6A, bottom panel). IP-10 treatment also inhibited the increase in JNK/SAPK activity mediated by RAFTK (Fig. 6B).

View larger version (32K): [in this window] [in a new window]   Fig. 6.   IP-10 inhibits the KSHV-GPCR-induced tyrosine phosphorylation of RAFTK and JNK kinase activity. The cells were transfected with KSHV-GPCR (10 µg), RAFTKWT (2 µg), and GST-JNK (1 µg). The transfected cells were treated with IP-10 for various time periods. A, top panel, the cell lysates from these samples were immunoprecipitated with anti-RAFTK antibody. Immunoprecipitates were separated by 7.5% SDS-PAGE and then blotted with anti-phosphotyrosine. The blots were then stripped and blotted with anti-RAFTK antibody (bottom panel). B, the lysates were subjected to JNK assay as described under "Experimental Procedures." Control lane represents immunoprecipitation with control antibody.

Our results indicate that in cells such as endothelium and B lymphocytes, in which RAFTK is expressed, RAFTK can act as an enhancer of KSHV-GPCR signaling, leading to JNK/SAPK activation, and can mediate the activation of cytoplasmic tyrosine kinases. Furthermore, these studies also suggest that distinct signaling pathways may regulate the activation of JNK/SAPK or p38 MAPK in response to this virus-encoded receptor, because RAFTK was found to mediate JNK/SAPK activation, not p38 MAPK activation. These observations provide insight into the molecular mechanisms whereby KSHV, via its constitutively activated GPCR, may be linked to important mediators of cell proliferation, such as JNK/SAPK kinase, and thereby foster the development of KS and B cell lymphoma.

	ACKNOWLEDGEMENTS

We thank Janet Delahanty for editing, Nancy DesRosiers for preparation of the figures, and Simone Jadusingh for typing the manuscript.

	FOOTNOTES

^* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^§ The first two authors contributed equally to this work.

To whom correspondence should be addressed: Division of Experimental Medicine and Hematology/Oncology, Harvard Institutes of Medicine-Beth Israel Deaconess Medical Center, 4 Blackfan Circle, Boston, MA 02115.

	ABBREVIATIONS

The abbreviations used are: KS, Kaposi's sarcoma; KSHV, KS-associated herpesvirus; GPCR, G protein-coupled receptor; GST, glutathione S-transferase; RAFTK, related adhesion focal tyrosine kinase; JNK, c-Jun amino-terminal kinase; SAPK, stress-activated protein kinase; MAPK, mitogen-activated protein kinase; IP-10, IFN--inducible protein-10; Pyk2, proline-rich tyrosine kinase 2; RAFTK^WT, wild-type RAFTK; RAFTK^m457, kinase-dead mutant RAFTK; RAFTK^m402, Src-binding mutant RAFTK; PAGE, polyacrylamide gel electrophoresis.

	REFERENCES

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