Research Assistant Professor, University of Michigan, Ann Arbor
Postdoctoral Research Fellow, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany,
Ph.D. Institute of Cytology, Russian Academy of Sciences, St.-Petersburg, 1993
Our current research is focused on the role of the hormone prolactin in the regulation of human breast cancer. In normal mammary development,prolactin (PRL) is critical for alveolar proliferation and differentiation. Increasing evidence supports the involvement of PRL in breastcancer,the leading type of cancer in women. The prolactin receptor (PRLR) is detected in 80% of human breast cancers and is overexpressed in breast cancercells.Normaland tumor mammary epithelial cellssynthesize PRL and PRLR,thus the PRL behaves as an autocrine growth factor for human breast cancercells. These results suggest the need for a more complete understanding of PRLR signaling in breast cancer. Tyrosine (Tyr) kinase JAK2 was identified as a PRLR-bound signaling molecule. Identification of the proteins recruited to the PRLR-JAK2 complex and dissection of the signaling pathways that are subsequently activated will ultimately provide a basis for understanding PRL action. We have found that the serine-threonine kinase PAK1 associates with and is Tyr phosphorylated by JAK2. We have identified three Tyr(s) of PAK1 which are phosphorylated by JAK2 using two-dimensional peptide mapping and MS/MS analysis. In an attempt to understand how PRL stimulates the growth of human breast cancer, we have shown that PAK1 regulates cyclin D1 promoter activity in response to PRL and have proposed two PAK1-dependent mechanisms for that: via nuclear translocation of Tyr-phosphorylated PAK1 and via formation of a Nck-PAK1 complex that sequesters PAK1 in the cytoplasm. We are continuing to work on this project. Another field of our interest is how PAK1 contributes to better cell migration, since tumor metastasis still remains the main cause of breast cancer death. We have shown that Tyr phosphorylation of PAK1 by JAK2 increases breast cancer cell motility and invasiveness, regulates the production of different MMPs, and changes cell adhesion. We want to know which signaling pathways link PRL/JAK2/PAK1 to breast cancer metastasis. Our studies may identify specific biomarkers that could make it easier to detect cancer cells with metastatic potential at an earlier stage or help doctors to know that they need to look at these particular molecules during clinical evaluations.
1. Freedlanskaya I.I.,Galactionov K.I.,Diakonova M.Y., Pinaev G.F. Microfilamin- a new cytoskeleton 53 kD protein. DANUSSR, 289(6), 1511-1513, 1986.
2. Poljanskaya G.G.,Diakonova M.Y. The influence of cultivation conditions on the karyotypic structure of a subline of rat kangaroo kidney cells. Tsitologia, 30(11), 1355-1363, 1988.
3. Diakonova M.Y., Sorkin A.D., Nikolsky N.N., Effect of primaquine on endocytosis of receptors of epidermal growth factor in A431 cells. Tsitologia, 34(7), p.63-69, 1992.
4. Diakonova M.Y., Sorkin A.D., Nikolsky N.N. Internalization of normal and mutant receptors of the platelet-derived growth factor. Tsitologia, 34(8), p.74-81, 1992.
5. Clement B.,Loreal O.,Rescan P.-Y.,Levavasseur F.,Diakonova M., Rissel M.,Helgoualc'h A.,Guillouzo A. Cellular origin of the hepatic extracellular matrix. In: Molecular and Cell Biology of Liver Fibrogenesis. Grenner Eds.,Kluver,UK, 1992.
6. Diakonova M.Y., Nikolsky N.N., Immunocytochemical study of the spontaneous and ligand-induced endocytosis of EGF-R in A431 cells, Tsitologia, 36(6), 74-81, 1994.
7. Diakonova M., B.Payrastre, A.van Velzen, W.J. Hage,P.van Bergen en Henegouwen, J.Boonstra, F.Cremers,B.Humbel. EGF induces rapid and transient association of PLC1 with EGF-receptor and filamentous actin at membrane ruffles of A431 cells. Journal of Cell Science, 108, 2499-2509, 1995 http://jcs.biologists.org/content/108/6/2499.full.pdf+html
8. Medvedeva N.,Chupreta S., Diakonova M., Tvorogov D., Blagovestschenskaia A., Nikolsky N. Action of nocodazol on redistribution of PLCy1 under mitogenic signal. Tsitologia, 39, 872-878, 1997.
9. Diakonova M., Chilov D., Arnautov A., Alexseyev V., Nikolsky N., Medvedeva N, Intracellular distribution of PLCy1 in cell lines with different level of transformation. Europ. J. Cell. Biol., 73, 360-367, 1997.
10. Diakonova M., Gerke V., Ernst J., Liautard J.-P., van der Vusse,G., Griffiths G. Localization of five annexins in J774macrophages and on isolated phagosomes. Journal of Cell Science, 110, 1199-1213, 1997 http://jcs.biologists.org/content/110/10/1199.full.pdf+html
11. Defacque H.,M. Egeberg,A. Huberman,M. Diakonova, C. Roy, P. Mangeat, W. Voelter, G. Marriott, J. Pfannsteil, H. Faulstich, G. Griffiths. Involvement of ezrin/moesin in de novo actin assembly on phagosomal membranes. The EMBO J., 19, 199-212, 2000. doi:10.1093/emboj/19.2.199 http://www.nature.com/emboj/journal/v19/n2/full/7592129a.html
12. Diakonova M.*, J. Herrington*, L. Rui, D. Gunter, C. Carter-Su. SH2-Bβ is required for growth hormone-induced actin reorganization. J. Biological Chemistry, 275, 13126-13133, 2000 (equal contribution). doi:10.1074/jbc.275.17.13126 http://www.jbc.org/content/275/17/13126.full?sid=9b51615f-46b2-4273-81f3-771a7af6a128
13. Carter-Su C.,L. Rui,J. Herrington,M. Stofega,M. Diakonova. Growth hormone signaling pathways. In "Targets for Growth Hormone and IGF-1 action", Ed R. Bouillon, 1-13, BioScientifica Ltd,Bristol, 2001.
14. Diakonova M., G. Bokoch, J.A. Swanson. Dynamics of cytockeletal proteins during Fcgamma-receptor-mediated phagocytosis in macrophages - Mol. Biol. of Cell, 13, 402-411, 2002.doi:10.1091/mbc.01-05-0273 http://www.molbiolcell.org/cgi/content/full/13/2/402
15. Diakonova M., D. R. Gunter, J. Herrington, C.Carter-Su. SH2-Bb is a Rac binding protein that regulates cell motility - J. Biol. Chem., 277, 10669-10677, 2002. doi:10.1074/jbc.M111138200 http://www.jbc.org/content/277/12/10669.full?sid=9b51615f-46b2-4273-81f3-771a7af6a128
16. O'Brien K.B.,L.S. Argetsinger,M. Diakonova, C. Carter-Su. YXXL motifs in SH2-Bbeta are phosphorylated by JAK2, JAK1, and platelet-derived growth factor receptor and are required for membrane ruffling. J. Biol. Chem, 278, 11970 - 11978, 2003. doi:10.1074/jbc.M210765200 http://www.jbc.org/content/278/14/11970.full?sid=9b51615f-46b2-4273-81f3-771a7af6a128
17. Reddy G. R.,M. J. Pushpanathan,R. F. Ransom,L. B. Holzman,F. C. Brosius III,M. Diakonova, P. Mathieson, M. A. Saleem, E. O. List, J. J. Kopchick, S. J. Frank, and R. K. Menon . Identification of the glomerular podocyte as a target for growth hormone action. Endocrinology, 148, 2045-2055, 2007. doi: 10.1210/en.2006-1285 http://endo.endojournals.org/content/148/5/2045.full
18. Diakonova M., E. Helfer, S. Seveau, J. Swanson, C. Kocks, L. Rui, M.-F. Carlier, C. Carter-Su. Adapter Protein SH2-Bbeta Stimulates Actin-based Motility of Listeria monocytogenes in a VASP-dependent Fashion. Infection and Immunity, 75, 3581-3593, 2007. doi:10.1128/IAI.00214-07. http://iai.asm.org/cgi/content/full/75/7/3581
19. Rider,L.,A. Shatrova,E. P. Feener,L. Webb and M. Diakonova. JAK2 Tyrosine Kinase Phosphorylates PAK1 and Regulates PAK1 Activity and Functions. J. Biol. Chem., 282, 30985-30996, 2007. doi: 10.1074/jbc.M701794200 http://www.jbc.org/content/282/42/30985.full?sid=51098893-973d-4c24-9402-a5a043a5445f
20. Kosik,A.,Bekier,M.E.,Katusin,J.D.,Kaur,H.,Zhou,X.,Diakonova, M., Chadee D.N., and Taylor, W.R. Investigating the role of Aurora kinases in RAS signaling. J. Cell Biochem. 106(1):33-41, 2009. doi: 10.1002/jcb.21974. http://onlinelibrary.wiley.com/doi/10.1002/jcb.21974/full
21. Rider L.,J. Tao,S. Snyder,B. Brinley,J. Lu and M. Diakonova. Adapter protein SH2B1β cross-links actin filaments and regulates actin cytoskeleton. Mol. Endocrinology, 23: 1065–1076, 2009.doi:10.1210/me.2008-0428 http://mend.endojournals.org/content/23/7/1065.full
22. Rider L. and M. Diakonova. Adapter protein SH2B1β binds Filamin A to regulate prolactin-dependent cytoskeletal reorganization and cell motility. Mol. Endocrinology, 25:1231-1243,2011. doi:10.1210/me.2011-0056 http://mend.endojournals.org/content/25/7/1231.full.pdf+html
23. Tao J.,Oladimeji P.,Rider L. and M. Diakonova. PAK1-Nck regulates cyclin D1 promoter activity in response to prolactin. Mol. Endocrinology, 25: 1565-1578, 2011 doi:10.1210/me.2011-0062 http://mend.endojournals.org/content/25/9/1565.full.pdf+html
24. Hammer A., Rider L., Oladimeji P., Cook L., Li Q., Mattingly R. and M. Diakonova. Tyrosyl phosphorylated PAK1 regulates breast cancer cell motility in response to prolactin through Filamin A. Mol. Endocrinology, 27: 455-465, 2013. doi: 10.1210/me.2012-1291 http://mend.endojournals.org/content/27/3/455.full.pdf+html
25. Rider L., Oladimeji P. and M. Diakonova. PAK1 regulates breast cancer cell invasion through secretion of matrix metalloproteinases in response to prolactin and three-dimensional collagen IV. Mol Endocrinology, 27:1048-64., 2013. doi: 10.1210/me.2012-132 http://mend.endojournals.org/content/27/7/1048.full.pdf+html
26. Diakonova M., P. Oladimeji and L. Rider. Prolactin regulates cycline D1 promoter activity via serine-threonine kinase PAK1 and adapter protein Nck. In: “Endocrine Diseases”, iConcept Press Lld., Hong-Kong, p121-145, 2014.
27. Jay J., Hammer A., Nestor-Kalinoski A. and M. Diakonova. JAK2 tyrosin kinase phosphorylates and is negatively regulated by centrosomal protein ninein. Mol Cell Biol. 2015 Jan; 35(1):111-31. doi: 10.1128/MCB.01138-14. PMID: 25332239.
28. Hammer A., Oladimeji P., De Las Casas L. E. and M. Diakonova. Phosphorylation of Tyrosine 285 of PAK1 facilitates βPIX/ GIT1 binding and regulates adhesion turnover. FASEB J. 2015 Mar; 29(3):943-59. doi: 10.1096/fj.14-259366. PMID:25466889.
29. Hammer A. and Diakonova M. Tyrosyl Phosphorylated Serine-Threonine Kinase PAK1 is a Novel Regulator of Prolactin-Dependent Breast Cancer Cell Motility and Invasion. In: “Recent Advances in Prolactin Research”, Springer, Switzerland. Editor: M. Diakonova, 2015; doi: 10.1007/978-3-319-12114-7_5. PMID: 25472536.
30. Hammer A.*, Laghate S* and Diakonova M. Src tyrosyl phosphorylates cortactin in response to prolactin. Biochem Biophys Res Commun. 2015, 463(4): 644-649. doi: 10.1016/j.bbrc.2015.05.116. PMID: 26043691. PMCID: PMC4497854
31. Oladimeji P., Kubohara Y., Kikuchi H., Oshima Y., Rusch C., Skerl R. and Diakonova M. A Derivative of Differentiation-inducing Factor-3 Inhibits PAK1 Activity and Breast Cancer Cell Proliferation. International Journal of Cancer and Clinical Research, 2015, 2:3. NIHMSID: NIHMS726981
Jenny Jay – Ph.D. student
Peter Oladimeji - Ph.D. student
Alan Hammer – Ph.D. student
Saba Barezi - Ph.D. student
Hamad Yadikar- Ph.D. student
Rose Henry - Master student