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. 1995 Jul;15(7):3644–3653. doi: 10.1128/mcb.15.7.3644

Mitogen-activated protein kinase activation is insufficient for growth factor receptor-mediated PC12 cell differentiation.

R R Vaillancourt 1, L E Heasley 1, J Zamarripa 1, B Storey 1, M Valius 1, A Kazlauskas 1, G L Johnson 1
PMCID: PMC230602  PMID: 7540718

Abstract

When expressed in PC12 cells, the platelet-derived growth factor beta receptor (beta PDGF-R) mediates cell differentiation. Mutational analysis of the beta PDGF-R indicated that persistent receptor stimulation of the Ras/Raf/mitogen-activated protein (MAP) kinase pathway alone was insufficient to sustain PC12 cell differentiation. PDGF receptor activation of signal pathways involving p60c-src or the persistent regulation of phospholipase C gamma was required for PC12 cell differentiation. beta PDGF-R regulation of phosphatidylinositol 3-kinase, the GTPase-activating protein of Ras, and the tyrosine phosphatase, Syp, was not required for PC12 cell differentiation. In contrast to overexpression of oncoproteins involved in regulating the MAP kinase pathway, growth factor receptor-mediated differentiation of PC12 cells requires the integration of other signals with the Ras/Raf/MAP kinase pathway.

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Selected References

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  1. Arvidsson A. K., Rupp E., Nånberg E., Downward J., Rönnstrand L., Wennström S., Schlessinger J., Heldin C. H., Claesson-Welsh L. Tyr-716 in the platelet-derived growth factor beta-receptor kinase insert is involved in GRB2 binding and Ras activation. Mol Cell Biol. 1994 Oct;14(10):6715–6726. doi: 10.1128/mcb.14.10.6715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Auger K. R., Serunian L. A., Soltoff S. P., Libby P., Cantley L. C. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell. 1989 Apr 7;57(1):167–175. doi: 10.1016/0092-8674(89)90182-7. [DOI] [PubMed] [Google Scholar]
  3. Bar-Sagi D., Feramisco J. R. Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation. Cell. 1985 Oct;42(3):841–848. doi: 10.1016/0092-8674(85)90280-6. [DOI] [PubMed] [Google Scholar]
  4. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  5. Chao M. V. Neurotrophin receptors: a window into neuronal differentiation. Neuron. 1992 Oct;9(4):583–593. doi: 10.1016/0896-6273(92)90023-7. [DOI] [PubMed] [Google Scholar]
  6. Claesson-Welsh L., Eriksson A., Morén A., Severinsson L., Ek B., Ostman A., Betsholtz C., Heldin C. H. cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules. Mol Cell Biol. 1988 Aug;8(8):3476–3486. doi: 10.1128/mcb.8.8.3476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Claesson-Welsh L., Eriksson A., Westermark B., Heldin C. H. cDNA cloning and expression of the human A-type platelet-derived growth factor (PDGF) receptor establishes structural similarity to the B-type PDGF receptor. Proc Natl Acad Sci U S A. 1989 Jul;86(13):4917–4921. doi: 10.1073/pnas.86.13.4917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coughlin S. R., Escobedo J. A., Williams L. T. Role of phosphatidylinositol kinase in PDGF receptor signal transduction. Science. 1989 Mar 3;243(4895):1191–1194. doi: 10.1126/science.2466336. [DOI] [PubMed] [Google Scholar]
  9. Countaway J. L., Nairn A. C., Davis R. J. Mechanism of desensitization of the epidermal growth factor receptor protein-tyrosine kinase. J Biol Chem. 1992 Jan 15;267(2):1129–1140. [PubMed] [Google Scholar]
  10. Cowley S., Paterson H., Kemp P., Marshall C. J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994 Jun 17;77(6):841–852. doi: 10.1016/0092-8674(94)90133-3. [DOI] [PubMed] [Google Scholar]
  11. Dikic I., Schlessinger J., Lax I. PC12 cells overexpressing the insulin receptor undergo insulin-dependent neuronal differentiation. Curr Biol. 1994 Aug 1;4(8):702–708. doi: 10.1016/s0960-9822(00)00155-x. [DOI] [PubMed] [Google Scholar]
  12. Escobedo J. A., Barr P. J., Williams L. T. Role of tyrosine kinase and membrane-spanning domains in signal transduction by the platelet-derived growth factor receptor. Mol Cell Biol. 1988 Dec;8(12):5126–5131. doi: 10.1128/mcb.8.12.5126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fanger G. R., Jones J. R., Maue R. A. Differential regulation of neuronal sodium channel expression by endogenous and exogenous tyrosine kinase receptors expressed in rat pheochromocytoma cells. J Neurosci. 1995 Jan;15(1 Pt 1):202–213. doi: 10.1523/JNEUROSCI.15-01-00202.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fantl W. J., Escobedo J. A., Williams L. T. Mutations of the platelet-derived growth factor receptor that cause a loss of ligand-induced conformational change, subtle changes in kinase activity, and impaired ability to stimulate DNA synthesis. Mol Cell Biol. 1989 Oct;9(10):4473–4478. doi: 10.1128/mcb.9.10.4473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fling S. P., Gregerson D. S. Peptide and protein molecular weight determination by electrophoresis using a high-molarity tris buffer system without urea. Anal Biochem. 1986 May 15;155(1):83–88. doi: 10.1016/0003-2697(86)90228-9. [DOI] [PubMed] [Google Scholar]
  16. Gardner A. M., Lange-Carter C. A., Vaillancourt R. R., Johnson G. L. Measuring activation of kinases in mitogen-activated protein kinase regulatory network. Methods Enzymol. 1994;238:258–270. doi: 10.1016/0076-6879(94)38024-4. [DOI] [PubMed] [Google Scholar]
  17. Greene L. A., Tischler A. S. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2424–2428. doi: 10.1073/pnas.73.7.2424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gronwald R. G., Grant F. J., Haldeman B. A., Hart C. E., O'Hara P. J., Hagen F. S., Ross R., Bowen-Pope D. F., Murray M. J. Cloning and expression of a cDNA coding for the human platelet-derived growth factor receptor: evidence for more than one receptor class. Proc Natl Acad Sci U S A. 1988 May;85(10):3435–3439. doi: 10.1073/pnas.85.10.3435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Heasley L. E., Johnson G. L. The beta-PDGF receptor induces neuronal differentiation of PC12 cells. Mol Biol Cell. 1992 May;3(5):545–553. doi: 10.1091/mbc.3.5.545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Heasley L. E., Senkfor S. I., Winitz S., Strasheim A., Teitelbaum I., Berl T. Hormonal regulation of MAP kinase in cultured rat inner medullary collecting tubule cells. Am J Physiol. 1994 Sep;267(3 Pt 2):F366–F373. doi: 10.1152/ajprenal.1994.267.3.F366. [DOI] [PubMed] [Google Scholar]
  21. Heldin C. H., Ernlund A., Rorsman C., Rönnstrand L. Dimerization of B-type platelet-derived growth factor receptors occurs after ligand binding and is closely associated with receptor kinase activation. J Biol Chem. 1989 May 25;264(15):8905–8912. [PubMed] [Google Scholar]
  22. Heldin C. H. Structural and functional studies on platelet-derived growth factor. EMBO J. 1992 Dec;11(12):4251–4259. doi: 10.1002/j.1460-2075.1992.tb05523.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hempstead B. L., Rabin S. J., Kaplan L., Reid S., Parada L. F., Kaplan D. R. Overexpression of the trk tyrosine kinase rapidly accelerates nerve growth factor-induced differentiation. Neuron. 1992 Nov;9(5):883–896. doi: 10.1016/0896-6273(92)90241-5. [DOI] [PubMed] [Google Scholar]
  24. Huff K., End D., Guroff G. Nerve growth factor-induced alteration in the response of PC12 pheochromocytoma cells to epidermal growth factor. J Cell Biol. 1981 Jan;88(1):189–198. doi: 10.1083/jcb.88.1.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ignelzi M. A., Jr, Miller D. R., Soriano P., Maness P. F. Impaired neurite outgrowth of src-minus cerebellar neurons on the cell adhesion molecule L1. Neuron. 1994 Apr;12(4):873–884. doi: 10.1016/0896-6273(94)90339-5. [DOI] [PubMed] [Google Scholar]
  26. Kaplan D. R., Morrison D. K., Wong G., McCormick F., Williams L. T. PDGF beta-receptor stimulates tyrosine phosphorylation of GAP and association of GAP with a signaling complex. Cell. 1990 Apr 6;61(1):125–133. doi: 10.1016/0092-8674(90)90220-9. [DOI] [PubMed] [Google Scholar]
  27. Kashishian A., Cooper J. A. Phosphorylation sites at the C-terminus of the platelet-derived growth factor receptor bind phospholipase C gamma 1. Mol Biol Cell. 1993 Jan;4(1):49–57. doi: 10.1091/mbc.4.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kashishian A., Kazlauskas A., Cooper J. A. Phosphorylation sites in the PDGF receptor with different specificities for binding GAP and PI3 kinase in vivo. EMBO J. 1992 Apr;11(4):1373–1382. doi: 10.1002/j.1460-2075.1992.tb05182.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kazlauskas A., Cooper J. A. Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins. Cell. 1989 Sep 22;58(6):1121–1133. doi: 10.1016/0092-8674(89)90510-2. [DOI] [PubMed] [Google Scholar]
  30. Kazlauskas A., Cooper J. A. Phosphorylation of the PDGF receptor beta subunit creates a tight binding site for phosphatidylinositol 3 kinase. EMBO J. 1990 Oct;9(10):3279–3286. doi: 10.1002/j.1460-2075.1990.tb07527.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kazlauskas A., Durden D. L., Cooper J. A. Functions of the major tyrosine phosphorylation site of the PDGF receptor beta subunit. Cell Regul. 1991 Jun;2(6):413–425. doi: 10.1091/mbc.2.6.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kazlauskas A., Ellis C., Pawson T., Cooper J. A. Binding of GAP to activated PDGF receptors. Science. 1990 Mar 30;247(4950):1578–1581. doi: 10.1126/science.2157284. [DOI] [PubMed] [Google Scholar]
  33. Kazlauskas A., Feng G. S., Pawson T., Valius M. The 64-kDa protein that associates with the platelet-derived growth factor receptor beta subunit via Tyr-1009 is the SH2-containing phosphotyrosine phosphatase Syp. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6939–6943. doi: 10.1073/pnas.90.15.6939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kelly J. D., Haldeman B. A., Grant F. J., Murray M. J., Seifert R. A., Bowen-Pope D. F., Cooper J. A., Kazlauskas A. Platelet-derived growth factor (PDGF) stimulates PDGF receptor subunit dimerization and intersubunit trans-phosphorylation. J Biol Chem. 1991 May 15;266(14):8987–8992. [PubMed] [Google Scholar]
  35. Kim J. W., Sim S. S., Kim U. H., Nishibe S., Wahl M. I., Carpenter G., Rhee S. G. Tyrosine residues in bovine phospholipase C-gamma phosphorylated by the epidermal growth factor receptor in vitro. J Biol Chem. 1990 Mar 5;265(7):3940–3943. [PubMed] [Google Scholar]
  36. Kimura K., Hattori S., Kabuyama Y., Shizawa Y., Takayanagi J., Nakamura S., Toki S., Matsuda Y., Onodera K., Fukui Y. Neurite outgrowth of PC12 cells is suppressed by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase. J Biol Chem. 1994 Jul 22;269(29):18961–18967. [PubMed] [Google Scholar]
  37. Kremer N. E., D'Arcangelo G., Thomas S. M., DeMarco M., Brugge J. S., Halegoua S. Signal transduction by nerve growth factor and fibroblast growth factor in PC12 cells requires a sequence of src and ras actions. J Cell Biol. 1991 Nov;115(3):809–819. doi: 10.1083/jcb.115.3.809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kypta R. M., Goldberg Y., Ulug E. T., Courtneidge S. A. Association between the PDGF receptor and members of the src family of tyrosine kinases. Cell. 1990 Aug 10;62(3):481–492. doi: 10.1016/0092-8674(90)90013-5. [DOI] [PubMed] [Google Scholar]
  39. Lazarovici P., Dickens G., Kuzuya H., Guroff G. Long-term, heterologous down-regulation of the epidermal growth factor receptor in PC12 cells by nerve growth factor. J Cell Biol. 1987 Jun;104(6):1611–1621. doi: 10.1083/jcb.104.6.1611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Lechleider R. J., Sugimoto S., Bennett A. M., Kashishian A. S., Cooper J. A., Shoelson S. E., Walsh C. T., Neel B. G. Activation of the SH2-containing phosphotyrosine phosphatase SH-PTP2 by its binding site, phosphotyrosine 1009, on the human platelet-derived growth factor receptor. J Biol Chem. 1993 Oct 15;268(29):21478–21481. [PubMed] [Google Scholar]
  41. Lee K. H., Bowen-Pope D. F., Reed R. R. Isolation and characterization of the alpha platelet-derived growth factor receptor from rat olfactory epithelium. Mol Cell Biol. 1990 May;10(5):2237–2246. doi: 10.1128/mcb.10.5.2237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Li B. Q., Kaplan D., Kung H. F., Kamata T. Nerve growth factor stimulation of the Ras-guanine nucleotide exchange factor and GAP activities. Science. 1992 Jun 5;256(5062):1456–1459. doi: 10.1126/science.1604323. [DOI] [PubMed] [Google Scholar]
  43. Li W., Nishimura R., Kashishian A., Batzer A. G., Kim W. J., Cooper J. A., Schlessinger J. A new function for a phosphotyrosine phosphatase: linking GRB2-Sos to a receptor tyrosine kinase. Mol Cell Biol. 1994 Jan;14(1):509–517. doi: 10.1128/mcb.14.1.509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Loeb D. M., Stephens R. M., Copeland T., Kaplan D. R., Greene L. A. A Trk nerve growth factor (NGF) receptor point mutation affecting interaction with phospholipase C-gamma 1 abolishes NGF-promoted peripherin induction but not neurite outgrowth. J Biol Chem. 1994 Mar 25;269(12):8901–8910. [PubMed] [Google Scholar]
  45. MacAuley A., Cooper J. A. The carboxy-terminal sequence of p56lck can regulate p60c-src. Mol Cell Biol. 1988 Aug;8(8):3560–3564. doi: 10.1128/mcb.8.8.3560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Matsui T., Heidaran M., Miki T., Popescu N., La Rochelle W., Kraus M., Pierce J., Aaronson S. Isolation of a novel receptor cDNA establishes the existence of two PDGF receptor genes. Science. 1989 Feb 10;243(4892):800–804. doi: 10.1126/science.2536956. [DOI] [PubMed] [Google Scholar]
  47. Miller A. D., Rosman G. J. Improved retroviral vectors for gene transfer and expression. Biotechniques. 1989 Oct;7(9):980-2, 984-6, 989-90. [PMC free article] [PubMed] [Google Scholar]
  48. Molloy C. J., Bottaro D. P., Fleming T. P., Marshall M. S., Gibbs J. B., Aaronson S. A. PDGF induction of tyrosine phosphorylation of GTPase activating protein. Nature. 1989 Dec 7;342(6250):711–714. doi: 10.1038/342711a0. [DOI] [PubMed] [Google Scholar]
  49. Mori S., Rönnstrand L., Yokote K., Engström A., Courtneidge S. A., Claesson-Welsh L., Heldin C. H. Identification of two juxtamembrane autophosphorylation sites in the PDGF beta-receptor; involvement in the interaction with Src family tyrosine kinases. EMBO J. 1993 Jun;12(6):2257–2264. doi: 10.1002/j.1460-2075.1993.tb05879.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Myles G. M., Brandt C. S., Carlberg K., Rohrschneider L. R. Tyrosine 569 in the c-Fms juxtamembrane domain is essential for kinase activity and macrophage colony-stimulating factor-dependent internalization. Mol Cell Biol. 1994 Jul;14(7):4843–4854. doi: 10.1128/mcb.14.7.4843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Nishimura R., Li W., Kashishian A., Mondino A., Zhou M., Cooper J., Schlessinger J. Two signaling molecules share a phosphotyrosine-containing binding site in the platelet-derived growth factor receptor. Mol Cell Biol. 1993 Nov;13(11):6889–6896. doi: 10.1128/mcb.13.11.6889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Noda M., Ko M., Ogura A., Liu D. G., Amano T., Takano T., Ikawa Y. Sarcoma viruses carrying ras oncogenes induce differentiation-associated properties in a neuronal cell line. Nature. 1985 Nov 7;318(6041):73–75. doi: 10.1038/318073a0. [DOI] [PubMed] [Google Scholar]
  53. Obermeier A., Bradshaw R. A., Seedorf K., Choidas A., Schlessinger J., Ullrich A. Neuronal differentiation signals are controlled by nerve growth factor receptor/Trk binding sites for SHC and PLC gamma. EMBO J. 1994 Apr 1;13(7):1585–1590. doi: 10.1002/j.1460-2075.1994.tb06421.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Obermeier A., Halfter H., Wiesmüller K. H., Jung G., Schlessinger J., Ullrich A. Tyrosine 785 is a major determinant of Trk--substrate interaction. EMBO J. 1993 Mar;12(3):933–941. doi: 10.1002/j.1460-2075.1993.tb05734.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Obermeier A., Lammers R., Wiesmüller K. H., Jung G., Schlessinger J., Ullrich A. Identification of Trk binding sites for SHC and phosphatidylinositol 3'-kinase and formation of a multimeric signaling complex. J Biol Chem. 1993 Nov 5;268(31):22963–22966. [PubMed] [Google Scholar]
  56. Pawson T., Schlessingert J. SH2 and SH3 domains. Curr Biol. 1993 Jul 1;3(7):434–442. doi: 10.1016/0960-9822(93)90350-w. [DOI] [PubMed] [Google Scholar]
  57. Qui M. S., Green S. H. PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity. Neuron. 1992 Oct;9(4):705–717. doi: 10.1016/0896-6273(92)90033-a. [DOI] [PubMed] [Google Scholar]
  58. Rönnstrand L., Mori S., Arridsson A. K., Eriksson A., Wernstedt C., Hellman U., Claesson-Welsh L., Heldin C. H. Identification of two C-terminal autophosphorylation sites in the PDGF beta-receptor: involvement in the interaction with phospholipase C-gamma. EMBO J. 1992 Nov;11(11):3911–3919. doi: 10.1002/j.1460-2075.1992.tb05484.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Stephens R. M., Loeb D. M., Copeland T. D., Pawson T., Greene L. A., Kaplan D. R. Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. Neuron. 1994 Mar;12(3):691–705. doi: 10.1016/0896-6273(94)90223-2. [DOI] [PubMed] [Google Scholar]
  60. Thomas S. M., DeMarco M., D'Arcangelo G., Halegoua S., Brugge J. S. Ras is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases. Cell. 1992 Mar 20;68(6):1031–1040. doi: 10.1016/0092-8674(92)90075-n. [DOI] [PubMed] [Google Scholar]
  61. Thomas S. M., Hayes M., D'Arcangelo G., Armstrong R. C., Meyer B. E., Zilberstein A., Brugge J. S., Halegoua S. Induction of neurite outgrowth by v-src mimics critical aspects of nerve growth factor-induced differentiation. Mol Cell Biol. 1991 Sep;11(9):4739–4750. doi: 10.1128/mcb.11.9.4739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Traverse S., Gomez N., Paterson H., Marshall C., Cohen P. Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem J. 1992 Dec 1;288(Pt 2):351–355. doi: 10.1042/bj2880351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Traverse S., Seedorf K., Paterson H., Marshall C. J., Cohen P., Ullrich A. EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr Biol. 1994 Aug 1;4(8):694–701. doi: 10.1016/s0960-9822(00)00154-8. [DOI] [PubMed] [Google Scholar]
  64. Vaillancourt R. R., Gardner A. M., Johnson G. L. B-Raf-dependent regulation of the MEK-1/mitogen-activated protein kinase pathway in PC12 cells and regulation by cyclic AMP. Mol Cell Biol. 1994 Oct;14(10):6522–6530. doi: 10.1128/mcb.14.10.6522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Vaillancourt R. R., Harwood A. E., Winitz S. Analysis of guanine nucleotides associated with protooncogene ras. Methods Enzymol. 1994;238:255–258. doi: 10.1016/0076-6879(94)38023-6. [DOI] [PubMed] [Google Scholar]
  66. Valius M., Bazenet C., Kazlauskas A. Tyrosines 1021 and 1009 are phosphorylation sites in the carboxy terminus of the platelet-derived growth factor receptor beta subunit and are required for binding of phospholipase C gamma and a 64-kilodalton protein, respectively. Mol Cell Biol. 1993 Jan;13(1):133–143. doi: 10.1128/mcb.13.1.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Valius M., Kazlauskas A. Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal. Cell. 1993 Apr 23;73(2):321–334. doi: 10.1016/0092-8674(93)90232-f. [DOI] [PubMed] [Google Scholar]
  68. Wahl M. I., Nishibe S., Kim J. W., Kim H., Rhee S. G., Carpenter G. Identification of two epidermal growth factor-sensitive tyrosine phosphorylation sites of phospholipase C-gamma in intact HSC-1 cells. J Biol Chem. 1990 Mar 5;265(7):3944–3948. [PubMed] [Google Scholar]
  69. Westermark B., Siegbahn A., Heldin C. H., Claesson-Welsh L. B-type receptor for platelet-derived growth factor mediates a chemotactic response by means of ligand-induced activation of the receptor protein-tyrosine kinase. Proc Natl Acad Sci U S A. 1990 Jan;87(1):128–132. doi: 10.1073/pnas.87.1.128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Wood K. W., Qi H., D'Arcangelo G., Armstrong R. C., Roberts T. M., Halegoua S. The cytoplasmic raf oncogene induces a neuronal phenotype in PC12 cells: a potential role for cellular raf kinases in neuronal growth factor signal transduction. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5016–5020. doi: 10.1073/pnas.90.11.5016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Wood K. W., Sarnecki C., Roberts T. M., Blenis J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell. 1992 Mar 20;68(6):1041–1050. doi: 10.1016/0092-8674(92)90076-o. [DOI] [PubMed] [Google Scholar]
  72. Yarden Y., Escobedo J. A., Kuang W. J., Yang-Feng T. L., Daniel T. O., Tremble P. M., Chen E. Y., Ando M. E., Harkins R. N., Francke U. Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature. 1986 Sep 18;323(6085):226–232. doi: 10.1038/323226a0. [DOI] [PubMed] [Google Scholar]
  73. Yokote K., Mori S., Hansen K., McGlade J., Pawson T., Heldin C. H., Claesson-Welsh L. Direct interaction between Shc and the platelet-derived growth factor beta-receptor. J Biol Chem. 1994 May 27;269(21):15337–15343. [PubMed] [Google Scholar]

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