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Endocrinology Vol. 138, No. 7 2835-2840
Copyright © 1997 by The Endocrine Society

ARTICLES

Proliferin Induces Endothelial Cell Chemotaxis through a G Protein-Coupled, Mitogen-Activated Protein Kinase-Dependent Pathway1

John C. Groskopf2, Li-Jyun Syu, Alan R. Saltiel and Daniel I. H. Linzer

Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University (J.C.G., D.I.H.L.), Evanston, Illinois 60208; and the Department of Signal Transduction, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co. (L.-J.S., A.R.S.), Ann Arbor, Michigan 48105

Address all correspondence and requests for reprints to: Dr. Daniel I. H. Linzer, Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2153 Sheridan Road, Evanston, Illinois 60208. E-mail: dlinzer{at}nwu.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
To investigate the mechanism of action of the placental angiogenic hormone proliferin (PLF), we analyzed the signaling components in endothelial cells that are required for PLF-induced chemotaxis. Pertussis toxin, which inactivates Gi proteins, inhibited PLF-induced chemotaxis of endothelial cells. Gi proteins can lead to activation of the mitogen-activated protein kinase (MAPK) pathway; PLF was found to stimulate MAPK activity, and this induction was blocked by both pertussis toxin and a specific inhibitor of MAPK kinase, PD 098059. Furthermore, a blockade of MAPK activation prevented endothelial cell movement in response to PLF. As PLF functionally interacts with the insulin-like growth factor II (IGF-II)/mannose 6-phosphate receptor, we also examined the effects of pertussis toxin and PD 098059 on another ligand for this receptor, a mutant form of IGF-II; both inhibitors also block the action of this factor on endothelial cells. These data suggest that chemotaxis initiated by PLF and mediated by the IGF-II/mannose 6-phosphate receptor occurs through a G protein-coupled pathway, and that MAPK activation is necessary for the chemotactic response.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ANGIOGENESIS, the growth of blood vessels from existing vessels, is essential for normal reproduction and development and is also involved in processes such as wound healing, tumor growth, and metastasis (1). Angiogenesis is tightly controlled by a number of positive and negative regulators (2), including the mouse placental hormones proliferin (PLF) and PLF-related protein (3). PLF, also referred to as mitogen-regulated protein (4), is a member of the PRL/GH family in the mouse (5) that is expressed specifically in the giant trophoblast cells of the mouse placenta, reaching peak levels at midgestation (6). PLF stimulates neovascularization in vivo and endothelial cell chemotaxis in culture; based on the chemotaxis assay, PLF represents the major angiogenic activity secreted by the midgestation mouse placenta (3). PLF binds to endothelial cells in the mouse placenta and is thus likely to be involved in the development of the placental vasculature (3).

The intracellular signaling pathways used by PLF are unknown. PLF binds to the insulin-like growth factor II (IGF-II)/mannose 6-phosphate (M6P) receptor (7), and interaction with this receptor is necessary for PLF-induced angiogenesis (8). The ability of the IGF-II/M6P receptor to function in signal transduction is controversial, though, as the cytoplasmic domain of this receptor lacks any known enzymatic activity. The mitogenic activity of IGF-II has generally been attributed to an interaction with the IGF-I receptor because IGF-II also binds this receptor with high affinity (9, 10), but some effects of IGF-II appear to be mediated through the IGF-II/M6P receptor (11, 12, 13, 14). Several reports have presented evidence that the IGF-II/M6P receptor can couple to G proteins (15, 16, 17), although this finding has subsequently been questioned (18). A mutant form of IGF-II, [Leu27]IGF-II, which binds to the IGF-II/M6P receptor, but not the IGF-I receptor (19, 20), can induce chemotaxis of rhabdomyosarcoma cells (21) and endothelial cells (8), but not DNA synthesis (20), suggesting that one of the specific functions of the IGF-II/M6P receptor is to regulate cell motility.

Both G protein-coupled receptors (22, 23, 24, 25, 26), including G protein-coupled receptors that mediate chemotaxis (27, 28, 29), and receptor tyrosine kinases (30) can stimulate the mitogen-activated protein kinase (MAPK) pathway. Activation of MAPK results from its phosphorylation by MAPK kinase (MEK), a process that can be blocked by the specific MEK inhibitor PD 098059 (31). The pathway from G protein-coupled receptors to MAPK activation involves the Gß{gamma}-dependent phosphorylation of Shc, a key component of the receptor tyrosine kinase-induced protein complex that activates ras, and thus the raf-MEK-MAPK pathway (32, 33).

Basic fibroblast growth factor (bFGF), a well characterized angiogenic factor that is both chemotactic and mitogenic for endothelial cells (34), is known to induce a pathway leading to the phosphorylation and activation of MAPK (35). In contrast to PLF, bFGF acts by binding to a receptor tyrosine kinase (35, 36). The ability of bFGF to induce endothelial cell mitogenesis can be blocked by the antiangiogenic factor 16K PRL (37), which inhibits bFGF-induced phosphorylation and activation of MAPK (38); these data suggest that MAPK activation is critical in endothelial cells for a mitogenic response to bFGF. Furthermore, Sa and Fox (39) found that bFGF-induced endothelial cell movement, but not mitogenesis, is blocked by pertussis toxin, which ADP-ribosylates G proteins of the Gi subclass and renders them inactive (40). Thus, distinct signaling mechanisms appear to be involved in the migratory and proliferative responses of endothelial cells to bFGF.

To characterize the signaling pathways used by PLF in endothelial cells, we have tested the involvement of G proteins and MAPK in PLF-induced chemotaxis.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell culture and reagents
Primary bovine capillary endothelial cells provided by Dr. J. Folkman (Harvard Medical School, Boston, MA) were propagated in gelatin-coated flasks in DMEM (Life Technologies, Grand Island, NY) supplemented with 10% FBS and 100 µg/ml endothelial cell mitogen (Biomedical Technologies, Stoughton, MA). Chinese hamster ovary cells expressing PLF-1 (CHO-PLF-1 cells) (7) were propagated in {alpha}MEM (Life Technologies) supplemented with 10% FBS and 5 µg/ml L-proline. The MEK inhibitor PD 098059 has been described previously (31). bFGF was purchased from R&D Systems (Minneapolis, MN), pertussis toxin and BSA were obtained from Sigma Chemical Co. (St. Louis, MO), and antibodies to Erk1 (C-16) and Erk2 (C-14) and protein A/G-agarose were purchased from Santa Cruz Biochemical (Santa Cruz, CA). [Leu27]IGF-II was generously provided by Dr. Katsuichi Sakano of Daiichi Pharmaceuticals (Tokyo, Japan).

Purification of PLF-1
CHO-PLF-1 cells were grown to confluence in T225 tissue culture flasks, washed with PBS, and fed with MCDB 302 (Life Technologies) containing 100 nM CdCl2 to stimulate transcription of the PLF-1 complementary DNA from the metallothionein gene promoter. The medium was collected and replaced with fresh medium daily for 3–4 days. Collected medium was clarified by centrifugation at 14,000 x g at 4 C, and 2 M ZnSO4 was added dropwise with stirring to a final concentration of 100 mM. The solution was stirred for 15 min at 4 C, then centrifuged 10 min at 14,000 x g; the pellet was resuspended in 0.5 M EDTA, pH 8.0 (1 ml for every 100 ml starting medium), dialyzed against 100 mM sodium phosphate, pH 8.0, and subjected to a series of chromatographic steps exactly as described by Lee and Nathans (7) to yield purified PLF-1 protein.

Endothelial cell chemotaxis assay
Endothelial cell migration was monitored as described previously (3, 8). Briefly, cells were incubated overnight in DMEM without serum but with 0.1% BSA, then collected. Test proteins were placed in the bottom well of a Boyden chamber (Neuroprobe, Cabin John, MD), and the chamber was assembled with gelatinized 0.5-µm filters (Nucleopore Corp., Pleasanton, CA); the concentrations of PLF, bFGF, and mutant IGF-II required for optimal induction of cell migration have been determined previously (3, 8). Cells were added to the top chamber (1.3 x 104 cells/well). After 6 h at 37 C, the filters were removed, fixed, and stained with Diff-Quik (Baxter Healthcare Corp., McGaw Park, IL), and the number of cells that had migrated to the lower surface of each filter in 10 high power fields was determined. Data were calculated as the mean ± SE. To assay the effects of inhibitors, cells were incubated for 30 min at room temperature on a nutator in the presence of pertussis toxin or PD 098059 before loading into the chamber. In experiments using PD 098509, all samples contained 0.5% dimethylsulfoxide (DMSO); this concentration of DMSO was determined to have no effect on cell migration.

MAPK assay
An in vitro kinase assay of immunoprecipitated MAPK was used as previously described (41). Subconfluent 60-mm dishes of endothelial cells were incubated overnight in DMEM without serum. The cells were then treated with test proteins or were first treated for 90 min with pertussis toxin or PD 098059 and then with test proteins. After treatment, the cells were harvested in 0.5 ml ice-cold lysis buffer [50 mM HEPES (pH 7.5), 150 mM NaCl, 5 mM EDTA, 1% Nonidet P-40, 0.5% sodium deoxycholate, 10 mM sodium pyrophosphate, 25 mM ß-glycerophosphate, 0.5 mM sodium vanadate, 50 mM NaF, 10 µg/ml aprotinin, 10 µg/ml leupeptin, 1 mM benzamidine, 0.5 mM phenylmethylsulfonyl fluoride, and 1 mM dithiothreitol], and the extracts were clarified by centrifugation. Antibodies against Erk1 and Erk2 (1 µg each) were added, and the samples were incubated at 4 C for 2 h on a nutator. Immune complexes were captured with protein A/G agarose, and kinase activity in the immune complexes was assayed in 50 µl 50 mM HEPES, 10 mM MgCl2, 2 mM EGTA, 1 mM dithiothreitol, 50 µM ATP with 100 µCi/ml [{gamma}-32P]ATP, and 20 µg myelin basic protein. After 10 min at 30 C, SDS sample buffer was added to stop the reaction. Samples were heated at 100 C for 3 min and then centrifuged, and the supernatants were subjected to SDS-PAGE. The amount of phosphorylated myelin basic protein was quantified by analysis of the dried gels on a PhosphorImager (Molecular Dynamics, Sunnyvale, CA). In experiments using PD 098509, all samples contained 0.5% DMSO; this concentration of DMSO was determined to have no effect on MAPK activity in the immune complex assay.

Mitogenesis assay
Endothelial cells were plated in 24-well dishes (1 x 104 cells/well) and incubated for 2 days in DMEM without serum but with 0.1% BSA. Cells were treated with mitogen for 8 h, then 1 µCi [3H]thymidine (DuPont-New England Nuclear, Wilmington, DE) was added for 4–6 h. Cells were washed twice in cold 5% trichloroacetic acid and solubilized in 0.25 N NaOH, and the uptake of the radioactive nucleoside was measured by scintillation counting.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Role of Gi in PLF-induced endothelial cell migration
The angiogenic activity of PLF involves an interaction of this hormone with the IGF-II/M6P receptor (8), which has been implicated in Gi protein activation (15, 16, 17). Initial experiments were, therefore, aimed at determining whether PLF-induced endothelial cell migration involved a G protein intermediate. PLF signaling through Gi would also be consistent with the ability of pertussis toxin to block chemotaxis of a number of cell types (42, 43, 44). As demonstrated previously (3), addition of PLF to endothelial cells in a Boyden chamber stimulated directed migration (Fig. 1AGo). Pertussis toxin caused a dose-dependent decrease in this response, and a concentration of 1 ng/ml pertussis toxin was sufficient to inhibit PLF-induced chemotaxis completely. Basal migration was unaffected by 1 ng/ml pertussis toxin, indicating that this treatment did not affect cell viability.



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  		Figure 1. Pertussis toxin inhibition of endothelial cell chemotaxis, but not DNA synthesis. A, Directed migration of endothelial cells in response to PLF (1 µg/ml) or bFGF (10 ng/ml) was assayed as described in Materials and Methods. Endothelial cells were incubated in the absence or presence of different concentrations of pertussis toxin (PT). The mean number of cells (±SE) that migrated per 10 high power fields in 4 independent chambers is shown. Basal migration (dashed line) reflects the level of random cell movement in the absence of an angiogenic factor. B, Endothelial cells were serum starved for 2 days, treated without or with pertussis toxin for 90 min, and then exposed to 10 ng/ml bFGF and [3H]thymidine. The amount of radioactivity incorporated is shown as the mean (±SE) from three measurements.

 
For comparison, the effect of pertussis toxin was also monitored in bFGF-treated cell cultures, and again, a dose-dependent inhibition of induced migration was observed (Fig. 1AGo). Although PLF, by itself, has little or no mitogenic effect on primary bovine capillary endothelial cells (Groskopf, J., and D. Jackson, unpublished observations), bFGF is able to induce DNA synthesis as well as migration in these cell cultures. Pertussis toxin had no effect on the mitogenic activity of bFGF (Fig. 1BGo), providing further evidence that the decrease in directed migration could not be attributed to decreased cell viability. These results indicate that PLF- and bFGF-induced chemotaxis (in contrast to bFGF-induced DNA synthesis) involve a Gi-dependent step.

PLF-induced activation of MAPK
Another possible component of the PLF signaling pathway leading to chemotaxis is MAPK, as MAPK activation can occur downstream of a pertussis toxin-sensitive G protein (23, 24, 25, 26, 27, 28, 29). Serum-starved endothelial cells were treated with PLF, and cell lysates were assayed for MAPK activity in an immune complex using myelin basic protein as the substrate. PLF induced MAPK activity within 5 min after treatment, and a peak of MAPK activity (3.5-fold above the level in untreated cells) was detected at approximately 15 min (Fig. 2Go). By 30 min, kinase activity had decreased to near-basal levels. Prior incubation of PLF with a monoclonal antibody that blocks PLF-stimulated cell migration (3) also abolished PLF-induced MAPK activation (data not shown). In contrast to these results with PLF, bFGF activated MAPK much more strongly; an increase in MAPK activity was observed within 2.5 min after treatment, peak levels (12-fold) were attained by 10 min, and MAPK activity remained elevated even at 60 min (Fig. 2Go).



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  		Figure 2. MAPK activation by PLF and bFGF. Endothelial cells that were serum starved overnight were treated with PLF (1 µg/ml) or bFGF (10 ng/ml) for various times. Cells were harvested, and MAPK activity was assayed in an immune complex with myelin basic protein (MBP) as substrate. MBP that was phosphorylated with [{gamma}-32P]ATP was visualized by PAGE and autoradiography.

 
If PLF stimulation of MAPK occurs through a Gi protein, then addition of pertussis toxin to PLF-treated endothelial cells should block an increase in MAPK activity. As predicted, no increase in MAPK activity was detected in lysates from endothelial cells treated with both PLF and pertussis toxin (Fig. 3Go). The effect of PD 098059, a specific inhibitor of MEK and, therefore, of MAPK activation (31), was also tested in this assay; PD 098059 was as effective as pertussis toxin in blocking MAPK activation (Fig. 3Go). In contrast, only PD 098059 (not pertussis toxin) was able to prevent bFGF-induced MAPK activation, consistent with bFGF stimulation of the MAPK pathway through a Gi-independent pathway.



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  		Figure 3. Effect of pertussis toxin and PD 098059 on PLF- and bFGF-induced MAPK activation. Endothelial cells that were serum starved overnight were treated with pertussis toxin (1 ng/ml) or PD 098059 (30 µM) for 90 min before stimulation with PLF (1 µg/ml for 15 min) or bFGF (10 ng/ml for 10 min). Cells were harvested, and MAPK activity was assayed in an immune complex with myelin basic protein (MBP) as substrate. MBP that was phosphorylated with [{gamma}-32P]ATP was visualized by PAGE and autoradiography.

 
Requirement for MAPK activation in PLF-induced endothelial cell chemotaxis
To determine whether the elevation in MAPK activity in response to PLF is required for a chemotactic response, endothelial cells were exposed to the specific MEK inhibitor PD 098059 and then treated with PLF. Similar to the effect of pertussis toxin, PD 098059 inhibited PLF-induced cell migration in a dose-dependent manner (Fig. 4AGo). This compound was also effective in blocking bFGF-stimulated migration, although a lower concentration of inhibitor was required to block completely the response to PLF (10 µM) than that to bFGF (30 µM). These concentrations of inhibitor are similar to those used to block MAPK activation in other cell types (31, 41). bFGF-induced mitogenesis was also blocked by PD 098059 (Fig. 4BGo), consistent with a requirement for MAPK activation in the induction of cell proliferation. Thus, MAPK activation is required for both PLF- and bFGF-induced chemotaxis as well as for bFGF mitogenesis in endothelial cell cultures.



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  		Figure 4. MEK inhibitor blockade of endothelial cell chemotaxis and DNA synthesis. A, PLF (1 µg/ml)- and bFGF (10 ng/ml)-induced endothelial cell chemotaxis was assayed in the absence or presence of varying concentrations of the MEK inhibitor (MEK I) PD 098509. The mean number of cells (±SE) that migrated per 10 high power fields in 4 independent chambers is shown. Basal migration (dashed line) reflects the level of random cell movement in the absence of an angiogenic factor. B, Endothelial cells were serum starved for 2 days, treated without or with PD 098059 for 90 min, and then exposed to 10 ng/ml bFGF and [3H]thymidine. The amount of radioactivity incorporated is shown as the mean (±SE) from three measurements.

 
IGF-II stimulation of chemotaxis
As PLF functionally interacts with the IGF-II/M6P receptor, other ligands for this receptor may also induce endothelial cell chemotaxis through a similar signaling pathway. [Leu27]IGF-II, a mutant form of IGF-II that binds to the IGF-II/M6P receptor but has greatly reduced affinity for the IGF-I receptor (19, 20), is chemotactic for endothelial cells (8). Directed migration of endothelial cells in response to [Leu27]IGF-II was effectively prevented by pertussis toxin and PD 098059 (Fig. 5Go). These results indicate that binding of either PLF or IGF-II to the IGF-II/M6P receptor on endothelial cells results in the activation of a Gi-coupled, MAPK-dependent signaling pathway, leading to chemotaxis.



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  		Figure 5. Endothelial cell chemotaxis in response to [Leu27]IGF-II is blocked by pertussis toxin and PD 098059. The directed migration of endothelial cells was measured in response to 30 ng/ml [Leu27]IGF-II in the presence of 1 ng/ml pertussis toxin (PT) or 10 µM PD 098059 (MEK I). The mean number of cells (±SE) that migrated per 10 high power fields in 4 independent chambers was determined. Basal migration in the absence of an angiogenic factor is indicated by the dashed line.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The data presented here reveal that endothelial cell chemotaxis induced by PLF as well as by bFGF and IGF-II occurs through a G protein-coupled, MAPK-dependent pathway. A role for pertussis toxin-sensitive G proteins in cell motility has been well established, and we now show that activation of MAPK is necessary for chemotaxis of endothelial cells in response to these factors. As PLF requires an interaction with the IGF-II/M6P receptor to stimulate endothelial cell migration (8), these results suggest that this receptor can couple to a G protein and lead to MAPK activation. The action of pertussis toxin is consistent with reports that G proteins of the Gi subclass are specifically activated through the IGF-II/M6P receptor upon binding of IGF-II (16, 17). Although PLF signaling may involve a receptor complex of which the IGF-II/M6P receptor is only one component, the finding that two ligands, PLF through its M6P moiety and IGF-II, that bind to distinct sites on this receptor (45, 46) each stimulate directed endothelial cell movement through similar pathways strongly argues that this receptor is itself transducing a signal.

The recent discovery of PD 098059 as a specific MEK inhibitor (31) has provided a valuable reagent for investigating the role of MAPK activation in various systems (47, 48). The high degree of specificity of PD 098059 appears to be due to a specific association with MEK, as this compound does not simply compete with ATP for binding to the kinase (Dudley, D., and A. Saltiel, unpublished results). PD 098059 blocked chemotaxis induced by PLF, providing the first evidence that MAPK activation is absolutely required for the chemotactic response. Consistent with the effect of PD 098059 on chemotaxis, PLF was able to induce MAPK activity in endothelial cells. PLF induced MAPK activity approximately 3.5-fold; this level is similar to that induced by other factors that act as only weak mitogens (49). The induction of MAPK activity by PLF was blocked by pertussis toxin, indicating that the IGF-II/M6P receptor can activate MAPK only through a Gi protein pathway.

Activation of MAPK by bFGF is required for both chemotactic and mitogenic effects. Relative to PLF, bFGF caused a more robust and prolonged induction of MAPK activity, consistent with the ability of bFGF to act as a potent mitogen for these cells. bFGF-induced MAPK activity and DNA synthesis were not sensitive to pertussis toxin, whereas the MEK inhibitor blocked both MAPK activation and DNA synthesis in bFGF-treated cells. The ability of pertussis toxin to prevent bFGF-induced cell migration while having no effect on MAPK activation and mitogenesis, and the ability of the MEK inhibitor to block both MAPK activation and chemotaxis indicate that MAPK activation is a necessary, but insufficient, step for endothelial cell chemotaxis. Thus, the FGF receptor can trigger two signaling pathways in endothelial cells: a G protein-dependent pathway necessary for chemotaxis, and a G protein-independent pathway leading to MAPK activation and entry of endothelial cells into S phase. These results demonstrate that PLF and bFGF, two angiogenic factors that bind to unrelated receptors, stimulate endothelial cell chemotaxis through similar signaling pathways.


   Acknowledgments
 
We thank Judah Folkman for providing bovine capillary endothelial cells, and Katsuichi Sakano of Daiichi Pharmaceuticals for the gift of [Leu27]IGF-II.


   Footnotes
 
1 This work was supported by Grant HD-24518 (to D.L.) and the P30 Research Center on Fertility and Infertility at Northwestern University (Grant HD-28048). Back

2 Supported as a predoctoral fellow in the Cellular and Molecular Basis of Disease Training Program (GM08061). Back

Received January 10, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Folkman J, Shing Y 1992 Angiogenesis. J Biol Chem 267:10931–10934[Free Full Text]
  2. Folkman J 1995 Clinical applications of research on angiogenesis. N Engl J Med 333:1757–1763[Free Full Text]
  3. Jackson D, Volpert OV, Bouck N, Linzer DIH 1994 Stimulation and inhibition of angiogenesis by placental proliferin and proliferin-related protein. Science 266:1581–1584[Abstract/Free Full Text]
  4. Parfett CLJ, Hamilton RT, Howell BW, Edwards DR, Nilsen-Hamilton M, Denhardt DT 1985 Characterization of a cDNA clone encoding murine mitogen-regulated protein: regulation of mRNA levels in mortal and immortal cell lines. Mol Cell Biol 5:3289–3292[Abstract/Free Full Text]
  5. Linzer DIH, Nathans D 1984 Nucleotide sequence of a growth-related member of the prolactin-growth hormone family. Proc Natl Acad Sci USA 81:4255–4259[Abstract/Free Full Text]
  6. Lee S-J, Talamantes F, Wilder E, Linzer DIH, Nathans D 1988 Trophoblastic giant cells of the mouse placenta as the site of proliferin synthesis. Endocrinology 122:1761–1768[Abstract]
  7. Lee S-J, Nathans D 1988 Proliferin secreted by cultured cells binds to mannose 6-phosphate receptors. J Biol Chem 263:3521–3527[Abstract/Free Full Text]
  8. Volpert O, Jackson D, Bouck N, Linzer DIH 1996 Requirement for the insulin-like growth factor II/mannose 6-phosphate receptor in proliferin-induced angiogenesis. Endocrinology 137:3871–3876[Abstract]
  9. Rechler MM, Zapf J, Nissley SP, Froesch ER, Moses AC, Podskalny JM, Schilling EE, Humbel RE 1980 Interactions of insulin-like growth factors I and II and multiplication-stimulating activity with receptors and serum carrier proteins. Endocrinology 107:1451–1459[Abstract]
  10. Conover CA, Misra P, Hintz RL, Rosenfeld RG 1986 Effect of an anti-insulin-like growth factor I receptor antibody on insulin-like growth factor II stimulation of DNA synthesis in human fibroblasts. Biochem Biophys Res Commun 139:501–508[CrossRef][Medline]
  11. Rogers SA, Purchio AF, Hammerman MR 1990 Mannose 6-phosphate-containing peptides activate phospholipase C in proximal tubular basolateral membranes from canine kidney. J Biol Chem 265:9722–9727[Abstract/Free Full Text]
  12. Hari J, Pierce SB, Morgan DO, Sara V, Smith MC, Roth RA 1987 The receptor for insulin-like growth factor II mediates an insulin-like response. EMBO J 6:3367–3371[Medline]
  13. Ishibe M, Rosier RN, Puzas JE 1991 Activation of osteoblast insulin-like growth factor-II/cation-independent mannose-6-phosphate receptors by specific phosphorylated sugars and antibodies induce insulin-like growth factor-II effects. Endocr Res 17:357–366[Medline]
  14. Rosenthal SM, Hsiao D, Silverman LA 1994 An insulin-like growth factor-II (IGF-II) analog with highly selective affinity for IGF-II receptors stimulates differentiation, but not IGF-I receptor down-regulation in muscle cells. Endocrinology 135:38–44[Abstract]
  15. Nishimoto I, Hata Y, Ogata E, Kojima I 1987 Insulin-like growth factor II stimulates calcium influx in competent BALB/c 3T3 cells primed with epidermal growth factor. Characteristics of calcium influx and involvement of GTP-binding protein. J Biol Chem 262:12120–12126[Abstract/Free Full Text]
  16. Okamoto T, Katada T, Murayama Y, Ui M, Ogata E, Nishimoto I 1990 A simple structure encodes G protein-activating function of the IGF-II/mannose 6-phosphate receptor. Cell 62:709–717[CrossRef][Medline]
  17. Ikezu T, Okamoto T, Giambarella U, Yokota T, Nishimoto I 1995 In vivo coupling of insulin-like growth factor II/mannose 6-phosphate receptor to heteromeric G proteins. Distinct roles of cytoplasmic domains and signal sequestration by the receptor. J Biol Chem 270:29224–29228[Abstract/Free Full Text]
  18. Körner C, Nürnberg B, Uhde M, Braulke T 1995 Mannose 6-phosphate/insulin-like growth factor II receptor fails to interact with G-proteins. Analysis of mutant cytoplasmic receptor domains. J Biol Chem 270:287–295[Abstract/Free Full Text]
  19. Sakano K, Enjoh T, Numata F, Fujiwara H, Marumoto Y, Higashihashi N, Sato Y, Perdue JF, Fujita-Yamaguchi Y 1991 The design, expression, and characterization of human insulin-like growth factor II (IGF-II) mutants specific for either the IGF-II/cation-independent mannose 6-phosphate receptor or IGF-I receptor. J Biol Chem 266:20626–20635[Abstract/Free Full Text]
  20. Beukers MW, Oh Y, Zhang H, Ling N, Rosenfeld RG 1991 [Leu27] insulin-like growth factor II is highly selective for the type-II IGF receptor in binding, cross-linking and thymidine incorporation experiments. Endocrinology 128:1201–1203[Abstract]
  21. Minniti CP, Kohn EC, Grubb JH, Sly WS, Oh Y, Müller HL, Rosenfeld RG, Helman LJ 1992 The insulin-like growth factor II (IGF-II)/mannose 6-phosphate receptor mediates IGF-II-induced motility in human rhabdomyosarcoma cells. J Biol Chem 267:9000–9004[Abstract/Free Full Text]
  22. Howe LR, Marshall CJ 1993 Lysophosphatidic acid stimulates mitogen-activated protein kinase activation via a G-protein-coupled pathway requiring p21ras and p74raf-1. J Biol Chem 268:20717–20720[Abstract/Free Full Text]
  23. van Corven EJ, Hordijk PL, Medema RH, Bos JL, Moolenaar WH 1993 Pertussis toxin-sensitive activation of p21ras by G protein-coupled receptor agonists in fibroblasts. Proc Natl Acad Sci USA 90:1257–1261[Abstract/Free Full Text]
  24. Cook SJ, Rubinfeld B, Albert I, McCormick F 1993 RapV12 antagonizes Ras-dependent activation of ERK1 and ERK2 by LPA and EGF in Rat-1 fibroblasts. EMBO J 12:3475–3485[Medline]
  25. Winitz S, Russell M, Qian N-X, Gardener A, Dywer L, Johnson GL 1993 Involvement of Ras and Raf in the Gi-coupled acetylcholine muscarinic m2 receptor activation of mitogen-activated protein (MAP) kinase kinase and MAP kinase. J Biol Chem 268:19196–19199[Abstract/Free Full Text]
  26. Honda Z, Takano T, Gotoh Y, Nishida E, Ito K, Shimizu T 1994 Transfected platelet-activating factor receptor activates mitogen-activated protein (MAP) kinase and MAP kinase kinase in Chinese hamster ovary cells. J Biol Chem 269:2307–2315[Abstract/Free Full Text]
  27. Torres M, Hall FL, O’ Neill K 1993 Stimulation of human neutrophils with formyl-methionyl-leucyl-phenylalanine induces tyrosine phosphorylation and activation of two distinct mitogen-activated protein-kinases. J Immunol 150:1563–1577[Abstract]
  28. Thompson HL, Shiroo M, Saklatvala J 1993 The chemotactic factor N-formylmethionyl-leucyl-phenylalanine activates microtubule-associated protein 2 (MAP) kinase and a MAP kinase kinase in polymorphonuclear leucocytes. Biochem J 290:483–488
  29. Buhl AM, Avdi N, Worthen GS, Johnson GL 1994 Mapping of the C5a receptor signal transduction network in human neutrophils. Proc Natl Acad Sci USA 91:9190–9194[Abstract/Free Full Text]
  30. Davis RJ 1994 MAPKs: new JNK expands the group. Trends Biochem Sci 19:470–473[CrossRef][Medline]
  31. Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR 1995 PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 270:27489–27484[Abstract/Free Full Text]
  32. van Biesen T, Hawes BE, Luttrell DK, Krueger KM, Touhara K, Porfiri E, Sakaue M, Luttrell LM, Lefkowitz RJ 1995 Receptor-tyrosine-kinase- and G beta gamma-mediated MAP kinase activation by a common signalling pathway. Nature 376:781–784[CrossRef][Medline]
  33. Touhara K, Hawes BE, van Biesen T, Lefkowitz RJ 1995 G protein beta gamma subunits stimulate phosphorylation of Shc adapter protein. Proc Natl Acad Sci USA 92:9284–9287[Abstract/Free Full Text]
  34. Friesel RE, Maciag T 1995 Molecular mechanisms of angiogenesis: fibroblast growth factor signal transduction. FASEB J 9:919–925[Abstract]
  35. Johnson DE, Williams LT 1993 Structural and functional diversity in the FGF receptor multigene family. Adv Canc Res 60:1–41[Medline]
  36. Vainikka S, Joukov V, Wennström S, Bergman M, Pelicci PG, Alitalo K 1994 Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. J Biol Chem 269:18320–18326[Abstract/Free Full Text]
  37. Ferrara N, Clapp C, Weiner R 1991 The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology 129:896–900[Abstract]
  38. D’Angelo G, Struman I, Martial J, Weiner RI 1995 Activation of mitogen-activated protein kinases by vascular endothelial growth factor and basic fibroblast growth factor in capillary endothelial cells is inhibited by the antiangiogenic factor 16-kDa N-terminal fragment of prolactin. Proc Natl Acad Sci USA 92:6374–6378[Abstract/Free Full Text]
  39. Sa G, Fox PL 1994 Basic fibroblast growth factor-stimulated endothelial cell movement is mediated by a pertussis toxin-sensitive pathway regulating phospholipase A2 activity. J Biol Chem 269:3219–3225[Abstract/Free Full Text]
  40. Neer EJ 1995 Heterotrimeric G proteins: organizers of transmembrane signals. Cell 80:249–257[CrossRef][Medline]
  41. Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR 1995 A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 92:7686–7689[Abstract/Free Full Text]
  42. Verghese MW, Charles L, Jakoi L, Dillon SB, Snyderman R 1987 Role of a guanine nucleotide regulatory protein in the activation of phospholipase C by different chemoattractants. J Immunol 138:4374–4380[Abstract]
  43. Schenk PW, Van Es S, Kesbeke F, Snaar-Jagalska BE 1991 Involvement of cyclic AMP cell surface receptors and G-proteins in signal transduction during slug migration of Dictyostelium discoideum. Dev Biol 145:110–118[CrossRef][Medline]
  44. Stracke ML, Kohn EC, Aznavoorian SA, Wilson LL, Saloman D, Krutzsch HC, Liotta LA, Schiffman E 1988 Insulin-like growth factors stimulate chemotaxis in human melanoma cells. Biochem Biophys Res Commun 153:1076–1083[CrossRef][Medline]
  45. MacDonald RG, Pfeffer SR, Coussens L, Tepper MA, Brocklebank CM, Mole JE, Anderson JK, Chen E, Czech MP, Ullrich A 1988 A single receptor binds both insulin-like growth factor II and mannose-6-phosphate. Science 239:1134–1137[Abstract/Free Full Text]
  46. Waheed A, Braulke T, Junghans U, von Figura K 1988 Mannose 6-phosphate/insulin like growth factor II receptor: the two types of ligands bind simultaneously to one receptor at different sites. Biochim Biophys Res Commun 152:1248–1254[CrossRef][Medline]
  47. Gould GW, Cuenda A, Thomson FJ, Cohen P 1995 The activation of distinct mitogen-activated protein kinase cascades is required for the stimulation of 2-deoxyglucose uptake by interleukin-1 and insulin-like growth factor-1 in KB cells. Biochem J 311:735–738
  48. Singh K, Balligand JL, Fischer TA, Smith TW, Kelly RA 1996 Regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvascular endothelial cells. Role of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT1 alpha. J Biol Chem 271:1111–1117[Abstract/Free Full Text]
  49. Luttrell LM, van Biesen T, Hawes BE, Koch WJ, Touhara K, Lefkowitz RJ 1995 G beta gamma subunits mediate mitogen-activated protein kinase activation by the tyrosine kinase insulin-like growth factor 1 receptor. J Biol Chem 270:16495–16498[Abstract/Free Full Text]



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