The Means laboratory is interested in the study of cell signaling cascades that regulate cell proliferation, differentiation or function and how alterations in these pathways contribute to development of cancer and other diseases such as obesity. It is hoped that an understanding of these pathways may provide clues to novel targets that may be amenable to drug discovery. Current major research projects under investigation include:

1. The cellular mechanisms that govern regulation of the CaM kinase cascade, which includes CaMKK, CaMKI, CaMKIV and AMPK. We investigate the cell surface receptor-mediated systems that elevate Ca2+, activate CaM and initiate pathways involving members of the CaM kinase cascade leading to transcriptional events that alter cell fate and/or function. Examples of such sub-projects now under investigation are how CaMKK/CaMKI regulates cell proliferation, CaMKK/CaMKIV affects brain development, CaMKK/CaMKIV regulates hematopoeitic stem cell homeostasis and CaMKK/AMPK influence food intake and energy expenditure.

2. Examining the role of the prolyl isomerase Pin1 in cell cycle regulation and oncogensis. Studies are focused on the Ras-mediated pathways involving Pin1 that control accumulation of critical cell cycle regulatory proteins such as c-Myc, cyclin E, p70S6K kinase and α 4 phosphatase and how deregulation of these proteins participate in human and mouse cell transformation and tumorigenesis. We are also interested in how signaling pathways involving Pin1 are involved in regulating cell migration and invasiveness. The pathways currently under investigation involve other Ras-related small G proteins such as Rac, Rho and/or Cdc42 and include evaluation of how these regulatory proteins impact the activities and functions of the MLK3 protein kinase and the Myosin II proteins.

Atchison , F.W., Capel, B., Means, A.R. (2003) Pin1 regulates the timing of the mammalian germ cell proliferation. Development 130:3579-3586

Yeh, ES, Cunningham, M, Arnold, H, Chasse, D, Monteith, T, Ivaldi, G, Hahn, WC, Stukenberg, PT, Shenolikar, SS, Uchida, T, Counter, CM, Nevins, JR, Means AR, Sears R (2004) A signalling pathway controlling Myc degradation that impacts oncogenic transformation of human cells. Nat. Cell. Biol. 6:308-318

Kahl, CR and Means, AR (2004) Regulation of cyclin D1/Cdk4 complexes by calcium/calmodulin dependent protein kinase I. J. Biol. Chem. 279:15411-15419

Kahl, CR and Means, AR (2004) Calcineurin regulates cycline D1 accumulation in growth-stimulated fibroblasts. Mol. Biol. Cell. 15:1833-1842

Anderson , KA, Noeldner, PK, Reece, K, Wadzinski, BE and Means, AR (2004) Regulation and Function of the Calcium/Calmodulin-dependent Protein Kinase IV/Protein Serine/Threonine Phosphatase 2A Signaling Complex. J Biol. Chem. 279:31708-31716

Pan, F., Means, A.R. and Liu, J.O. (2005) Calmodulin-dependent protein kinase IV regulates nuclear export of Cabin1 during T-cell activation. EMBO J. 15:2014-2013.

Chow, F.A., Anderson , K.A., Noeldner, P.K. and Means, A.R. (2005) The autonomous activity of calcium/calmodulin-dependent protein kinase IV is required for its role in transcription. J. Biol. Chem. 280:20530-20538.

Hurley, R.L., Anderson , K.A., Franzone, J.M., Kemp, B.E., Means, A.R., and Witters, L.A. (2005) The Ca 2+ /Calmodulin-dependent Protein Kinase Kinases Are AMP-activated Protein Kinase Kinases. J. Biol. Chem. 280:29060-29066

Kitsos, C.M., Sankar, U., Illario, M., Colomer-Font, J.M., Duncan , A.W., Ribar, T.J., Reya,T., and Means, A.R. (2005) Calmodulin-dependent protein kinase IV regulates hematopoietic stem cell maintenance. J. Biol. Chem. 280:33101-33108

Yi, P., Wu, R.-C., Sandquist, J., Wong, J., Tsai, S.Y., Tsai, M.-J., Means, A.R. and O'Malley, B.W. (2005) Peptidyl-prolyl Isomerase 1 (Pin1) serves as a coactivator of steroid receptor by regulating the activity of posphorylated steroid receptor coactivator-3 (SRC-3/AIB1). Mol. Cell. Biol. 25: 9687-9699

Yeh, E.S., Lew, B.O., Means, A.R. (2006) The loss of PIN1 deregulates cyclin E and sensitizes MEFs to genomic instability. J. Biol. Chem. 281: 241 – 251

van Drogen, F., Sanfelt, O., Malyukova A., Matskova, L, Yeh, E., Means, A.R. and Reed, S.I. (2006) Ubiquitylation of Cyclin E requires the sequential function of SCF complexes containing distinct hCdc4 isoforms. Mol. Cell. 23:37-48

Sandquist, J.C., Swenson, K.I., Demali, K.A., Burridge, K. and Means, A.R. (2006) Rho kinase diefferentially regulates phosphorylation of nonmuscle myosin II isoforms A and B during cell rouding and migration. J. Biol. Chem. 281:35873-35883. 

Hurley, R.L., Barre, L.K., Wood, S.D., Anderson, K.A., Kemp, B.E., Means, A.R. and Witters, L.A. (2006) Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP. J. Biol. Chem. 281:36662-36672.

Yeh, E.S. and Means, A.R. (2007) Pin1, the cell cycle and cancer.  Nat Rev Cancer 7:381-388

Phan, R.T, Saito, M., Kitagawa, Y., Means, A.R. and Dalla-Favera, R.  (2007)  Genotoxic stress regulates expression of the proto-oncogene BcI6 in germinal center B cells.  Nature Immunology – Nat Immunol.  8(10):1132-9. Epub 2007 Sep 9.

Illario M, Giardino-Torchia ML, Sankar U, Ribar TJ, Galgani M, Vitiello L, Masci AM, Bertani FR, Ciaglia E, Astone D, Maulucci G, Cavallo A, Vitale M, Cimini V, Pastore L, Means AR, Rossi G, Racioppi   L. (2007)  Calmodulin-dependent kinase IV links toll-like receptor 4 signaling with survival pathway of activated denditric cells.  Blood 111:723-731.  Epub 2007 Oct 1.

Reineke, E.L., Lam, M., Liu, Q., Liu, Y., Stanya, K.J., Chang, K.S., Means, A.R. and Kao, H.Y. (2007)  Degradation of the tumor suppressor PML by Pin1 contributes to the cancer phenotype of breast cancer MDA-MB-231 cells.  Mol Cell Biol Nov 26: [Epub ahead of print)