M.S., Altay State University (Russia), 1982

Ph.D., Institute of Organic Chemistry (Moscow), 1987

Previous studies from our laboratory demonstrated that ligand-dependent and úindependent signal transduction pathways may differentially regulate Stat5a and Stat5b nuclear translocation and retention. Prl-dependent activation of Stat5a and Stat5b was dependent on JAK2 activation and resulted in punctate detergent-resistant nuclear complexes in COS and HeLa cells. In contrast, the selective translocation of Stat5b to the nucleus following Src and Bcr/Abl activation did not appear to be dependent on JAK2 activation. Analysis of Stat5a and Stat5b chimeric proteins suggested that the determinant responsible for these differences resides in the C-terminal half of the protein.
Then, we postulated that the regulation of specific gene targets involved in proliferation, differentiation or apoptosis by these two highly related isoforms of Stat5 might also reflect their activation by different signal transduction pathways. The DNA-binding properties of the two closely related Stat5 proteins, Stat5a and Stat5b, induced either by Prl or by Src were analyzed by electrophoretic mobility shift assays using several different Stat5 binding sites. Src-induced Stat5b DNA-binding complexes consistently displayed a slightly faster mobility than those induced by Prl, as well as differences in their ability to be supershifted by anti-Stat5 antibodies. IP-Westerns performed using specific antibodies directed at the N- and C-termini of Stat5b suggested that depending on the activating stimulus, Stat5b exhibited different conformations, which influenced antibody accessibility at its C-terminus. These conformational differences may in part be due to differential effects of Prl and Src on Stat5b tyrosine phosphorylation, since Src induced several additional sites of tyrosine phosphorylation of Stat5b at residues other than Y699, including Y724 and Y679. The latter Y679 is conserved in all mammalian Stat5b's, but is not present in Stat5a. We have also observed that Stat5b potentiated Src-induced cytoskeletal and morphological changes in transiently transfected HeLa cells, which were not observed using Stat5a or a C-truncated isoform, Stat5D40. Thus, depending on the signal transduction pathway responsible for activation, different conformations of activated Stat5 may result in selective biological responses.

Kabotyanski EB, Hutter M, Xian W, Rijnkels M, and Rosen JM
Integration of prolactin and glucocorticoid signaling at the ß-casein promoter and enhancer by ordered
recruitment of specific transcription factors and chromatin modifiers
Mol Endo. 2006; 20(10):2355–2368. [PDF]

Kabotyanski EB, Rosen JM.
Signal transduction pathways regulated by prolactin and Src result in different conformations of activated Stat5b.
J Biol Chem. 2003 May 9;278(19):17218-27. [PDF]

Grimm SL, Seagroves TN, Kabotyanski EB, Hovey RC, Vonderhaar BK, Lydon JP, Miyoshi K, Hennighausen L, Ormandy CJ, Lee AV, Stull MA, Wood TL, Rosen JM.
Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development.
Mol Endocrinol. 2002 Dec;16(12):2675-91. [PDF]

Kazansky AV, Kabotyanski EB, Wyszomierski SL, Mancini MA, Rosen JM.
Differential effects of prolactin and src/abl kinases on the nuclear translocation of STAT5B and STAT5A.
J Biol Chem. 1999 Aug 6;274(32):22484-92. [PDF]

Kabotyanski EB, Gomelsky L, Han JO, Stamato TD, Roth DB.
Double-strand break repair in Ku86- and XRCC4-deficient cells.
Nucleic Acids Res. 1998 Dec 1;26(23):5333-42.

Kabotyanski EB, Zhu C, Kallick DA, Roth DB.
Hairpin opening by single-strand-specific nucleases.
Nucleic Acids Res. 1995 Oct 11;23(19):3872-81.