This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Blake, R. A. Articles by Courtneidge, S. A. Search for Related Content PubMed PubMed Citation Articles by Blake, R. A. Articles by Courtneidge, S. A.

Src Promotes PKC Degradation

SUGEN Inc., South San Francisco, California 94080-4811 [R. A. B., S. A. C.], and Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom [P. G-P., P. J. P.]

Platelet-derived growth factor BB (PDGF) stimulates DNA synthesis through a mechanism that is at least partially dependent upon Src family tyrosine kinases, although the signal transduction pathway downstream of Src is poorly understood. We have studied the signaling between Src and different protein kinase C (PKC) isoforms and its possible role in the regulation of PDGF-stimulated DNA synthesis. We found that Src promoted the tyrosine phosphorylation of PKC, and its subsequent degradation. Enforced expression of PKC inhibited PDGF-stimulated DNA synthesis, whereas expression of PKC and PKC did not, a finding consistent with a model in which PKC negatively regulates G₁-to-S-phase progression. We used mutagenesis to map a critical Src phosphorylation site on PKC to tyrosine 311. A mutant form of PKC in which tyrosine 311 was replaced with phenylalanine (Y311F) was more stable in the presence of Src, suggesting that Src-induced degradation was a direct result of PKC tyrosine phosphorylation. We conclude that PKC is downstream of Src but is unlikely to play a positive role in the signaling pathway by which Src promotes DNA synthesis.

This article has been cited by other articles:

				A. Cataldi, V. Di Giacomo, M. Rapino, S. Zara, and R. A. Rana Ionizing Radiation Induces Apoptotic Signal Through Protein Kinase C{delta} (delta) and Survival Signal Through Akt and Cyclic-Nucleotide Response Element-Binding Protein (CREB) in Jurkat T Cells Biol. Bull., October 1, 2009; 217(2): 202 - 212. [Abstract] [Full Text] [PDF]

				S. Van Schaeybroeck, D. M. Kelly, J. Kyula, S. Stokesberry, D. A. Fennell, P. G. Johnston, and D. B. Longley Src and ADAM-17-Mediated Shedding of Transforming Growth Factor-{alpha} Is a Mechanism of Acute Resistance to TRAIL Cancer Res., October 15, 2008; 68(20): 8312 - 8321. [Abstract] [Full Text] [PDF]

				H. Nakashima, G. D. Frank, H. Shirai, A. Hinoki, S. Higuchi, H. Ohtsu, K. Eguchi, A. Sanjay, M. E. Reyland, P. J. Dempsey, et al. Novel Role of Protein Kinase C-{delta} Tyr311 Phosphorylation in Vascular Smooth Muscle Cell Hypertrophy by Angiotensin II Hypertension, February 1, 2008; 51(2): 232 - 238. [Abstract] [Full Text] [PDF]

				M. Morita, H. Matsuzaki, T. Yamamoto, Y. Fukami, and U. Kikkawa Epidermal Growth Factor Receptor Phosphorylates Protein Kinase C {delta} at Tyr332 to form a Trimeric Complex with p66Shc in the H2O2-stimulated Cells J. Biochem., January 1, 2008; 143(1): 31 - 38. [Abstract] [Full Text] [PDF]

				L. Cao, K. Yu, C. Banh, V. Nguyen, A. Ritz, B. J. Raphael, Y. Kawakami, T. Kawakami, and A. R. Salomon Quantitative Time-Resolved Phosphoproteomic Analysis of Mast Cell Signaling J. Immunol., November 1, 2007; 179(9): 5864 - 5876. [Abstract] [Full Text] [PDF]

				S. Kaul, V. Anantharam, Y. Yang, C. J. Choi, A. Kanthasamy, and A. G. Kanthasamy Tyrosine Phosphorylation Regulates the Proteolytic Activation of Protein Kinase C{delta} in Dopaminergic Neuronal Cells J. Biol. Chem., August 5, 2005; 280(31): 28721 - 28730. [Abstract] [Full Text] [PDF]

				S. Murugappan, H. Shankar, S. Bhamidipati, R. T. Dorsam, J. Jin, and S. P. Kunapuli Molecular mechanism and functional implications of thrombin-mediated tyrosine phosphorylation of PKC{delta} in platelets Blood, July 15, 2005; 106(2): 550 - 557. [Abstract] [Full Text] [PDF]

				K. Wheaton and K. Riabowol Protein Kinase C{delta} Blocks Immediate-Early Gene Expression in Senescent Cells by Inactivating Serum Response Factor Mol. Cell. Biol., August 15, 2004; 24(16): 7298 - 7311. [Abstract] [Full Text] [PDF]

				B. Li, X. Wang, N. Rasheed, Y. Hu, S. Boast, T. Ishii, K. Nakayama, K. I. Nakayama, and S. P. Goff Distinct roles of c-Abl and Atm in oxidative stress response are mediated by protein kinase C {delta} Genes & Dev., August 1, 2004; 18(15): 1824 - 1837. [Abstract] [Full Text] [PDF]

				V. O. Rybin, J. Guo, A. Sabri, H. Elouardighi, E. Schaefer, and S. F. Steinberg Stimulus-specific Differences in Protein Kinase C{delta} Localization and Activation Mechanisms in Cardiomyocytes J. Biol. Chem., April 30, 2004; 279(18): 19350 - 19361. [Abstract] [Full Text] [PDF]

				C. N. Wrobel, J. Debnath, E. Lin, S. Beausoleil, M. F. Roussel, and J. S. Brugge Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture J. Cell Biol., April 26, 2004; 165(2): 263 - 273. [Abstract] [Full Text] [PDF]

				D. N. JACKSON and D. A. FOSTER The enigmatic protein kinase C{delta}: complex roles in cell proliferation and survival FASEB J, April 1, 2004; 18(6): 627 - 636. [Abstract] [Full Text] [PDF]

				T. Kajimoto, Y. Shirai, N. Sakai, T. Yamamoto, H. Matsuzaki, U. Kikkawa, and N. Saito Ceramide-induced Apoptosis by Translocation, Phosphorylation, and Activation of Protein Kinase C{delta} in the Golgi Complex J. Biol. Chem., March 26, 2004; 279(13): 12668 - 12676. [Abstract] [Full Text] [PDF]

				M. Sumitomo, T. Asano, J. Asakuma, T. Asano, D. M. Nanus, and M. Hayakawa Chemosensitization of Androgen-Independent Prostate Cancer with Neutral Endopeptidase Clin. Cancer Res., January 1, 2004; 10(1): 260 - 266. [Abstract] [Full Text] [PDF]

				J. A. Tapia, L. J. Garcia-Marin, and R. T. Jensen Cholecystokinin-stimulated Protein Kinase C-{delta} Kinase Activation, Tyrosine Phosphorylation, and Translocation Are Mediated by Src Tyrosine Kinases in Pancreatic Acinar Cells J. Biol. Chem., September 12, 2003; 278(37): 35220 - 35230. [Abstract] [Full Text] [PDF]

				G. Yamaura, T. Turoczi, F. Yamamoto, M. A. Q. Siddqui, N. Maulik, and D. K. Das STAT signaling in ischemic heart: a role of STAT5A in ischemic preconditioning Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H476 - H482. [Abstract] [Full Text] [PDF]

				D. Crosby and A. W. Poole Physical and Functional Interaction between Protein Kinase C {delta} and Fyn Tyrosine Kinase in Human Platelets J. Biol. Chem., June 27, 2003; 278(27): 24533 - 24541. [Abstract] [Full Text] [PDF]

				X.-L. Tang, E. Kodani, H. Takano, M. Hill, K. Shinmura, T. M. Vondriska, P. Ping, and R. Bolli Protein tyrosine kinase signaling is necessary for NO donor-induced late preconditioning against myocardial stunning Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1441 - H1448. [Abstract] [Full Text] [PDF]

				J. Bao, G. Gur, and Y. Yarden Src promotes destruction of c-Cbl: Implications for oncogenic synergy between Src and growth factor receptors PNAS, March 4, 2003; 100(5): 2438 - 2443. [Abstract] [Full Text] [PDF]

				I. Junttila, R. P. Bourette, L. R. Rohrschneider, and O. Silvennoinen M-CSF induced differentiation of myeloid precursor cells involves activation of PKC-{delta} and expression of Pkare J. Leukoc. Biol., February 1, 2003; 73(2): 281 - 288. [Abstract] [Full Text] [PDF]

				Y. Shibukawa, M. Takahashi, I. Laffont, K. Honke, and N. Taniguchi Down-regulation of Hydrogen Peroxide-induced PKCdelta Activation in N-Acetylglucosaminyltransferase III-transfected HeLaS3 Cells J. Biol. Chem., January 24, 2003; 278(5): 3197 - 3203. [Abstract] [Full Text] [PDF]

				E. Joseloff, C. Cataisson, H. Aamodt, H. Ocheni, P. Blumberg, A. J. Kraker, and S. H. Yuspa Src Family Kinases Phosphorylate Protein Kinase C delta on Tyrosine Residues and Modify the Neoplastic Phenotype of Skin Keratinocytes J. Biol. Chem., March 29, 2002; 277(14): 12318 - 12323. [Abstract] [Full Text] [PDF]

				M. Blass, I. Kronfeld, G. Kazimirsky, P. M. Blumberg, and C. Brodie Tyrosine Phosphorylation of Protein Kinase C{delta} Is Essential for Its Apoptotic Effect in Response to Etoposide Mol. Cell. Biol., January 1, 2002; 22(1): 182 - 195. [Abstract] [Full Text] [PDF]

				M. W. Wooten, M. L. Vandenplas, M. L. Seibenhener, T. Geetha, and M. T. Diaz-Meco Nerve Growth Factor Stimulates Multisite Tyrosine Phosphorylation and Activation of the Atypical Protein Kinase C's via a src Kinase Pathway Mol. Cell. Biol., December 15, 2001; 21(24): 8414 - 8427. [Abstract] [Full Text] [PDF]

				S. Wakino, U. Kintscher, Z. Liu, S. Kim, F. Yin, M. Ohba, T. Kuroki, A. H. Schonthal, W. A. Hsueh, and R. E. Law Peroxisome Proliferator-activated Receptor gamma Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cdelta Pathway in Vascular Smooth Muscle Cells J. Biol. Chem., December 7, 2001; 276(50): 47650 - 47657. [Abstract] [Full Text] [PDF]

				Y. Saito, J. Haendeler, Y. Hojo, K. Yamamoto, and B. C. Berk Receptor Heterodimerization: Essential Mechanism for Platelet-Derived Growth Factor-Induced Epidermal Growth Factor Receptor Transactivation Mol. Cell. Biol., October 1, 2001; 21(19): 6387 - 6394. [Abstract] [Full Text] [PDF]

				R. Hattori, H. Otani, T. Uchiyama, H. Imamura, J. Cui, N. Maulik, G. A. Cordis, L. Zhu, and D. K. Das Src tyrosine kinase is the trigger but not the mediator of ischemic preconditioning Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1066 - H1074. [Abstract] [Full Text] [PDF]

				C. M. Boney, H. Sekimoto, P. A. Gruppuso, and A. R. Frackelton Jr. Src Family Tyrosine Kinases Participate in Insulin-like Growth Factor I Mitogenic Signaling in 3T3-L1 Cells Cell Growth Differ., July 1, 2001; 12(7): 379 - 386. [Abstract] [Full Text] [PDF]

				C. Benes and S. P. Soltoff Modulation of PKC{delta} tyrosine phosphorylation and activity in salivary and PC-12 cells by Src kinases Am J Physiol Cell Physiol, June 1, 2001; 280(6): C1498 - C1510. [Abstract] [Full Text] [PDF]

				H. Konishi, E. Yamauchi, H. Taniguchi, T. Yamamoto, H. Matsuzaki, Y. Takemura, K. Ohmae, U. Kikkawa, and Y. Nishizuka Phosphorylation sites of protein kinase C delta in H2O2-treated cells and its activation by tyrosine kinase invitro PNAS, May 24, 2001; (2001) 111158798. [Abstract] [Full Text] [PDF]

				M. Zhong, Z. Lu, T. Abbas, A. Hornia, K. Chatakondu, N. Barile, P. Kaplan, and D. A. Foster Novel Tumor-promoting Property of Tamoxifen Cell Growth Differ., April 1, 2001; 12(4): 187 - 192. [Abstract] [Full Text]

				R. A. Blake, M. A. Broome, X. Liu, J. Wu, M. Gishizky, L. Sun, and S. A. Courtneidge SU6656, a Selective Src Family Kinase Inhibitor, Used To Probe Growth Factor Signaling Mol. Cell. Biol., December 1, 2000; 20(23): 9018 - 9027. [Abstract] [Full Text] [PDF]

				M. Sumitomo, R. Shen, J. S. Goldberg, J. Dai, D. Navarro, and D. M. Nanus Neutral Endopeptidase Promotes Phorbol Ester-induced Apoptosis in Prostate Cancer Cells by Inhibiting Neuropeptide-induced Protein Kinase C {{delta}} Degradation Cancer Res., December 1, 2000; 60(23): 6590 - 6596. [Abstract] [Full Text]

				M. A. Otieno and T. W. Kensler A Role for Protein Kinase C-{{delta}} in the Regulation of Ornithine Decarboxylase Expression by Oxidative Stress Cancer Res., August 1, 2000; 60(16): 4391 - 4396. [Abstract] [Full Text]

				A. Hornia, Z. Lu, T. Sukezane, M. Zhong, T. Joseph, P. Frankel, and D. A. Foster Antagonistic Effects of Protein Kinase C alpha and delta on Both Transformation and Phospholipase D Activity Mediated by the Epidermal Growth Factor Receptor Mol. Cell. Biol., November 1, 1999; 19(11): 7672 - 7680. [Abstract] [Full Text] [PDF]

				C. Bahr, A. Rohwer, L. Stempka, G. Rincke, F. Marks, and M. Gschwendt DIK, a Novel Protein Kinase That Interacts with Protein Kinase Cdelta . CLONING, CHARACTERIZATION, AND GENE ANALYSIS J. Biol. Chem., November 10, 2000; 275(46): 36350 - 36357. [Abstract] [Full Text] [PDF]

				I. Kronfeld, G. Kazimirsky, P. S. Lorenzo, S. H. Garfield, P. M. Blumberg, and C. Brodie Phosphorylation of Protein Kinase Cdelta on Distinct Tyrosine Residues Regulates Specific Cellular Functions J. Biol. Chem., November 3, 2000; 275(45): 35491 - 35498. [Abstract] [Full Text] [PDF]

				A. M. Pepio and W. S. Sossin Membrane Translocation of Novel Protein Kinase Cs Is Regulated by Phosphorylation of the C2 Domain J. Biol. Chem., February 2, 2001; 276(6): 3846 - 3855. [Abstract] [Full Text] [PDF]

				S. P. Soltoff Rottlerin Is a Mitochondrial Uncoupler That Decreases Cellular ATP Levels and Indirectly Blocks Protein Kinase Cdelta Tyrosine Phosphorylation J. Biol. Chem., October 5, 2001; 276(41): 37986 - 37992. [Abstract] [Full Text] [PDF]

				H. Konishi, E. Yamauchi, H. Taniguchi, T. Yamamoto, H. Matsuzaki, Y. Takemura, K. Ohmae, U. Kikkawa, and Y. Nishizuka Phosphorylation sites of protein kinase C delta in H2O2-treated cells and its activation by tyrosine kinase invitro PNAS, June 5, 2001; 98(12): 6587 - 6592. [Abstract] [Full Text] [PDF]