A Novel Stat3 Binding Motif in Gab2 Mediates Transformation of Primary Hematopoietic Cells by the Stk/Ron Receptor Tyrosine Kinase in Response to Friend Virus Infection

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2007 Mar 14

PMID 17353274

Citations 17

Authors

Shuang Ni

Chunmei Zhao

Gen-Sheng Feng

Robert F Paulson

Pamela H Correll

Affiliations

Soon will be listed here.

Abstract

Friend erythroleukemia virus has long served as a paradigm for the study of the multistage progression of leukemia. Friend virus infects erythroid progenitor cells, followed by an initial polyclonal expansion of infected cells, which is driven by the activation of a naturally occurring truncated form of the Stk receptor tyrosine kinase (Sf-Stk). Subsequently, the accumulation of additional mutations in p53 and the activation of PU.1 result in full leukemic transformation. The early stages of transformation induced by Friend virus are characterized in vitro by the Epo-independent growth of infected erythroblasts. We have shown previously that this transforming event requires the kinase activity and Grb2 binding site of Sf-Stk and the recruitment of a Grb2/Gab2 complex to Sf-Stk. Here, we demonstrate that Stat3 is required for the Epo-independent growth of Friend virus-infected cells and that the activation of Stat3 by Sf-Stk is mediated by a novel Stat3 binding site in Gab2. These results underscore a central role for Stat3 in hematopoietic transformation and describe a previously unidentified role for Gab2 in the recruitment and activation of Stat3 in response to transforming signals generated by tyrosine kinases.

Citing Articles

Crizotinib Has Preclinical Efficacy in Philadelphia-Negative Myeloproliferative Neoplasms.

Gurska L, Okabe R, Schurer A, Tong M, Soto M, Choi D Clin Cancer Res. 2022; 29(5):943-956.

PMID: 36537918 PMC: 9992133. DOI: 10.1158/1078-0432.CCR-22-1763.

STAT3 roles in viral infection: antiviral or proviral?.

Chang Z, Wang Y, Zhou X, Long J Future Virol. 2020; 13(8):557-574.

PMID: 32201498 PMC: 7079998. DOI: 10.2217/fvl-2018-0033.

Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer.

Li X, Mak V, Zhou Y, Wang C, Wong E, Sharma R Nat Commun. 2019; 10(1):716.

PMID: 30755611 PMC: 6372715. DOI: 10.1038/s41467-019-08574-7.

A Central Role for STAT3 in Gammaherpesvirus-Life Cycle and -Diseases.

Li X, Bhaduri-McIntosh S Front Microbiol. 2016; 7:1052.

PMID: 27458446 PMC: 4937026. DOI: 10.3389/fmicb.2016.01052.

Structure and function of Gab2 and its role in cancer (Review).

Ding C, Yu W, Feng J, Luo J Mol Med Rep. 2015; 12(3):4007-4014.

PMID: 26095858 PMC: 4526075. DOI: 10.3892/mmr.2015.3951.

References

Zhu Q, Robinson L, Roginskaya V, Corey S . G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses. Blood. 2003; 103(9):3305-12. DOI: 10.1182/blood-2003-06-1861. View

Casteran N, De Sepulveda P, Beslu N, Aoubala M, Letard S, Lecocq E . Signal transduction by several KIT juxtamembrane domain mutations. Oncogene. 2003; 22(30):4710-22. DOI: 10.1038/sj.onc.1206587. View

Million R, Harakawa N, Roumiantsev S, Varticovski L, Van Etten R . A direct binding site for Grb2 contributes to transformation and leukemogenesis by the Tel-Abl (ETV6-Abl) tyrosine kinase. Mol Cell Biol. 2004; 24(11):4685-95. PMC: 416425. DOI: 10.1128/MCB.24.11.4685-4695.2004. View

Li J, DAndrea A, Lodish H, Baltimore D . Activation of cell growth by binding of Friend spleen focus-forming virus gp55 glycoprotein to the erythropoietin receptor. Nature. 1990; 343(6260):762-4. DOI: 10.1038/343762a0. View

Ohashi T, Masuda M, Ruscetti S . Induction of sequence-specific DNA-binding factors by erythropoietin and the spleen focus-forming virus. Blood. 1995; 85(6):1454-62. View

Kirito K, Uchida M, Yamada M, Miura Y, Komatsu N . A distinct function of STAT proteins in erythropoietin signal transduction. J Biol Chem. 1997; 272(26):16507-13. DOI: 10.1074/jbc.272.26.16507. View

Yamamura Y, Senda H, Kageyama Y, Matsuzaki T, Noda M, Ikawa Y . Erythropoietin and Friend virus gp55 activate different JAK/STAT pathways through the erythropoietin receptor in erythroid cells. Mol Cell Biol. 1998; 18(3):1172-80. PMC: 108830. DOI: 10.1128/MCB.18.3.1172. View

Bromberg J, Horvath C, Besser D, Lathem W, Darnell Jr J . Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol. 1998; 18(5):2553-8. PMC: 110635. DOI: 10.1128/MCB.18.5.2553. View

Kirito K, Uchida M, Takatoku M, Nakajima K, Hirano T, Miura Y . A novel function of Stat1 and Stat3 proteins in erythropoietin-induced erythroid differentiation of a human leukemia cell line. Blood. 1998; 92(2):462-71. View

10.

Besser D, Bromberg J, Darnell Jr J, Hanafusa H . A single amino acid substitution in the v-Eyk intracellular domain results in activation of Stat3 and enhances cellular transformation. Mol Cell Biol. 1999; 19(2):1401-9. PMC: 116068. DOI: 10.1128/MCB.19.2.1401. View

11.

Bromberg J, Wrzeszczynska M, Devgan G, Zhao Y, Pestell R, Albanese C . Stat3 as an oncogene. Cell. 1999; 98(3):295-303. DOI: 10.1016/s0092-8674(00)81959-5. View

12.

Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H . Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J. 1999; 18(17):4657-68. PMC: 1171539. DOI: 10.1093/emboj/18.17.4657. View

13.

Persons D, Paulson R, Loyd M, Herley M, Bodner S, Bernstein A . Fv2 encodes a truncated form of the Stk receptor tyrosine kinase. Nat Genet. 1999; 23(2):159-65. DOI: 10.1038/13787. View

14.

Halupa A, Bailey M, Huang K, Iscove N, Levy D, Barber D . A novel role for STAT1 in regulating murine erythropoiesis: deletion of STAT1 results in overall reduction of erythroid progenitors and alters their distribution. Blood. 2004; 105(2):552-61. DOI: 10.1182/blood-2003-09-3237. View

15.

Lenox L, Perry J, Paulson R . BMP4 and Madh5 regulate the erythroid response to acute anemia. Blood. 2004; 105(7):2741-8. DOI: 10.1182/blood-2004-02-0703. View

16.

Chiarle R, Simmons W, Cai H, Dhall G, Zamo A, Raz R . Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat Med. 2005; 11(6):623-9. DOI: 10.1038/nm1249. View

17.

Subramanian A, Teal H, Correll P, Paulson R . Resistance to friend virus-induced erythroleukemia in W/W(v) mice is caused by a spleen-specific defect which results in a severe reduction in target cells and a lack of Sf-Stk expression. J Virol. 2005; 79(23):14586-94. PMC: 1287579. DOI: 10.1128/JVI.79.23.14586-14594.2005. View

18.

Zhang J, Randall M, Loyd M, Li W, Schweers R, Persons D . Role of erythropoietin receptor signaling in Friend virus-induced erythroblastosis and polycythemia. Blood. 2005; 107(1):73-8. PMC: 1392603. DOI: 10.1182/blood-2005-05-1784. View

19.

Bentires-Alj M, Gil S, Chan R, Wang Z, Wang Y, Imanaka N . A role for the scaffolding adapter GAB2 in breast cancer. Nat Med. 2005; 12(1):114-21. DOI: 10.1038/nm1341. View

20.

Yu M, Lowell C, Neel B, Gu H . Scaffolding adapter Grb2-associated binder 2 requires Syk to transmit signals from FcepsilonRI. J Immunol. 2006; 176(4):2421-9. DOI: 10.4049/jimmunol.176.4.2421. View