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 two hormones - prolactin and
estrogen - in the regulation of human breast cancer. We want to know which signaling
pathways link these two hormones to tyrosine kinase JAK2 and serine-threonine kinase
PAK1 and 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.
We are interested in the regulation of PAK1 protein by JAK2 kinase. JAK2 is a tyrosine kinase that is activated by approximately two-third of the cytokine superfamily of receptors. For many of these receptors, activation of JAK2 is the initiating step in ligand-dependent signaling. Serine-threonine kinase PAK1 has been implicated in a wide range of biological functions including apoptosis and malignant transformation, cell morphology and motility, and the stress response. Although both proteins – JAK2 and PAK1 –have been implicated in the regulation of cell pathways that can lead to breast cancer but how they work together and the precise mechanism of their action is unknown. Our long term goal is to understand the molecular mechanisms that control cell division and cell motility and disregulation of which leads to human breast cancer. Toward this aim, we have started to analyze the relationship between JAK2 and PAK1. We showed that JAK2 binds to PAK1 and makes PAK1 more active. Activated PAK1 contributes to better cell survival that may promote cancer development. Our lab studies how JAK2 and PAK1 increase cell proliferation, cell motility that leads to metastasis and/or ability of cells where PAK1 protein is hyperactivated by JAK2 protein, to produce breast tumors in animals. In understanding of how these proteins work together will help to design new therapeutic approaches and possibly drugs for treatment of human breast cancer.
We are also excited by our findings that activated JAK2 plays a role on centrosomes (Jay et. al., 2015). It has been shown that a V617F gain-of-function point mutation of JAK2 is the cause of ~90% of all polycythemia vera cases and ~50% of all essential thrombocythemia and primitive myelofibrosis cases. Despite of multiple reports describing the contribution of JAK2 V617F to different pathologies, a comprehensive mechanism has remained elusive. We plan to establish collaboration with hematologic oncologists who will provide us samples, assistance and discussion of potential clinical relevance of the centrosome-located activated JAK2 in chronic myeloproliferative disorders, especially polycythemia vera.
Megan Dreier, Ph.D.
Current Laboratory Grants:
NIH R01 DK88127 Role of JAK2-PAK1 interaction in prolactin-depending signaling
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
32. Oladimeji P., R. Skerl, C. Rusch and M. Diakonova. The role of tyrosyl phosphorylated PAK1 in the synergetic effect of estrogen and prolactin in breast cancer cells. Cancer Research 2016, 76(9): 2600-11. doi: 10.1158/0008-5472.CAN-15-1758. PMID: 26944939
33. Oladimeji P and Diakonova M. PAK1 translocates into nucleus in response to prolactin but not to estrogen.<http://www.ncbi.nlm.nih.gov/pubmed/27003261> Biochem Biophys Res Commun. 473 (1): 206-11, 2016. doi: 10.1016/j.bbrc.2016.03.079. PMID: 27003261.NIHMS 772746.
34. Hammer A. and M. Diakonova. Prolactin-induced PAK1 tyrosyl phosphorylation promotes FAK dephosphorylation, breast cancer cell motility, invasion and metastasis. BMC Cell Biology, 17(1):31, 2016. doi: 10.1186/s12860-016-0109-5