C-Abl is an Effector of Src for Growth Factor-induced C-myc Expression and DNA Synthesis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2002 Feb 16

PMID 11847100

Citations 52

Authors

Olivia Furstoss

Karel Dorey

Valerie Simon

Daniela Barila

Giulio Superti-Furga

Serge Roche

Affiliations

Soon will be listed here.

Abstract

The mechanism by which the ubiquitously expressed Src family kinases regulate mitogenesis is not well understood. Here we report that cytoplasmic tyrosine kinase c-Abl is an important effector of c-Src for PDGF- and serum-induced DNA synthesis. Inactivation of cytoplasmic c-Abl by the kinase-inactive Abl-PP-K(-) (AblP242E/P249E/K290M) or by microinjection of Abl neutralizing antibodies inhibited mitogenesis. The kinase-inactive SrcK295M induced a G(1) block that was overcome by the constitutively active Abl-PP (AblP242E/P249E). Conversely, the inhibitory effect of Abl-PP-K(-) was not compensated by Src. c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function. Finally, we found that p53 inactivation and c-myc expression, two cell cycle events regulated by Src during mitogenesis, also implied c-Abl: c-Abl function was dispensable in cells deficient in active p53 and inhibition of c-Abl reduced mitogen-induced c-myc expression. These data identify a novel function of cytoplasmic c-Abl in the signalling pathways regulating growth factor-induced c-myc expression and we propose the existence of a tyrosine kinase signalling cascade (PDGFR/c-Src/c-Abl) important for mitogenesis.

Citing Articles

ABL1 and ABL2 promote medulloblastoma leptomeningeal dissemination.

Jones J, Zhang H, Lyne A, Cavalli F, Hassen W, Stevenson K Neurooncol Adv. 2023; 5(1):vdad095.

PMID: 37781087 PMC: 10540884. DOI: 10.1093/noajnl/vdad095.

Oncogenic Signalling of PEAK2 Pseudokinase in Colon Cancer.

Lecointre C, Fourgous E, Montarras I, Kerneur C, Simon V, Boublik Y Cancers (Basel). 2022; 14(12).

PMID: 35740644 PMC: 9221080. DOI: 10.3390/cancers14122981.

Combating acquired resistance to MAPK inhibitors in melanoma by targeting Abl1/2-mediated reactivation of MEK/ERK/MYC signaling.

Tripathi R, Liu Z, Jain A, Lyon A, Meeks C, Richards D Nat Commun. 2020; 11(1):5463.

PMID: 33122628 PMC: 7596241. DOI: 10.1038/s41467-020-19075-3.

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment.

Karim M, Liao E, Kim J, Meints J, Martinez H, Pletnikova O Mol Neurodegener. 2020; 15(1):27.

PMID: 32299471 PMC: 7164361. DOI: 10.1186/s13024-020-00364-w.

CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo.

Alajati A, DAmbrosio M, Troiani M, Mosole S, Pellegrini L, Chen J J Clin Invest. 2020; 130(5):2435-2450.

PMID: 32250342 PMC: 7190998. DOI: 10.1172/JCI131133.

References

Pepperkok R, Ansorge W, Courtneidge S . The Src family tyrosine kinases are required for platelet-derived growth factor-mediated signal transduction in NIH 3T3 cells. Proc Natl Acad Sci U S A. 1993; 90(16):7696-700. PMC: 47209. DOI: 10.1073/pnas.90.16.7696. View

Endo K, Takeshita T, Kasai H, Sasaki Y, Tanaka N, Asao H . STAM2, a new member of the STAM family, binding to the Janus kinases. FEBS Lett. 2000; 477(1-2):55-61. DOI: 10.1016/s0014-5793(00)01760-9. View

Sawyers C, McLaughlin J, Goga A, Havlik M, Witte O . The nuclear tyrosine kinase c-Abl negatively regulates cell growth. Cell. 1994; 77(1):121-31. DOI: 10.1016/0092-8674(94)90240-2. View

Wang X, Sato R, Brown M, Hua X, Goldstein J . SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell. 1994; 77(1):53-62. DOI: 10.1016/0092-8674(94)90234-8. View

Treisman R . Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev. 1994; 4(1):96-101. DOI: 10.1016/0959-437x(94)90097-3. View

Roche S, Koegl M, Barone M, Roussel M, Courtneidge S . DNA synthesis induced by some but not all growth factors requires Src family protein tyrosine kinases. Mol Cell Biol. 1995; 15(2):1102-9. PMC: 232016. DOI: 10.1128/MCB.15.2.1102. View

van der Geer P, Hunter T, Lindberg R . Receptor protein-tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol. 1994; 10:251-337. DOI: 10.1146/annurev.cb.10.110194.001343. View

Wong K, Zou X, Merrell K, Patel A, Marcu K, Chellappan S . v-Abl activates c-myc transcription through the E2F site. Mol Cell Biol. 1995; 15(12):6535-44. PMC: 230906. DOI: 10.1128/MCB.15.12.6535. View

Barone M, Courtneidge S . Myc but not Fos rescue of PDGF signalling block caused by kinase-inactive Src. Nature. 1995; 378(6556):509-12. DOI: 10.1038/378509a0. View

10.

Wen S, Jackson P, Van Etten R . The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products. EMBO J. 1996; 15(7):1583-95. PMC: 450068. View

11.

Druker B, Tamura S, Buchdunger E, Ohno S, Segal G, Fanning S . Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996; 2(5):561-6. DOI: 10.1038/nm0596-561. View

12.

Broome M, Hunter T . Requirement for c-Src catalytic activity and the SH3 domain in platelet-derived growth factor BB and epidermal growth factor mitogenic signaling. J Biol Chem. 1996; 271(28):16798-806. DOI: 10.1074/jbc.271.28.16798. View

13.

Yuan Z, Huang Y, Whang Y, Sawyers C, Weichselbaum R, Kharbanda S . Role for c-Abl tyrosine kinase in growth arrest response to DNA damage. Nature. 1996; 382(6588):272-4. DOI: 10.1038/382272a0. View

14.

Roche S, McGlade J, Jones M, Gish G, Pawson T, Courtneidge S . Requirement of phospholipase C gamma, the tyrosine phosphatase Syp and the adaptor proteins Shc and Nck for PDGF-induced DNA synthesis: evidence for the existence of Ras-dependent and Ras-independent pathways. EMBO J. 1996; 15(18):4940-8. PMC: 452231. View

15.

Lewis J, Baskaran R, Taagepera S, Schwartz M, Wang J . Integrin regulation of c-Abl tyrosine kinase activity and cytoplasmic-nuclear transport. Proc Natl Acad Sci U S A. 1996; 93(26):15174-9. PMC: 26376. DOI: 10.1073/pnas.93.26.15174. View

16.

Gotoh N, Toyoda M, Shibuya M . Tyrosine phosphorylation sites at amino acids 239 and 240 of Shc are involved in epidermal growth factor-induced mitogenic signaling that is distinct from Ras/mitogen-activated protein kinase activation. Mol Cell Biol. 1997; 17(4):1824-31. PMC: 232029. DOI: 10.1128/MCB.17.4.1824. View

17.

Takeshita T, Arita T, Higuchi M, Asao H, Endo K, Kuroda H . STAM, signal transducing adaptor molecule, is associated with Janus kinases and involved in signaling for cell growth and c-myc induction. Immunity. 1997; 6(4):449-57. DOI: 10.1016/s1074-7613(00)80288-5. View

18.

Zindy F, Quelle D, Roussel M, Sherr C . Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene. 1997; 15(2):203-11. DOI: 10.1038/sj.onc.1201178. View

19.

Barila D, Superti-Furga G . An intramolecular SH3-domain interaction regulates c-Abl activity. Nat Genet. 1998; 18(3):280-2. DOI: 10.1038/ng0398-280. View

20.

Koleske A, Gifford A, Scott M, Nee M, Bronson R, Miczek K . Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron. 1999; 21(6):1259-72. DOI: 10.1016/s0896-6273(00)80646-7. View