Lawrence Quilliam, Ph.D.
Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
John D. Van Nuys Medical Science Building
635 Barnhill Drive, Room 4075
Indianapolis, Indiana 46202-5126
Phone: (317) 274-8550
Facsimile: (317) 274-4686
B.S. in Biochemistry, 1983, University of Manchester, U.K.
Ph. D. in Biochemistry, 1986, University of Sheffield, U.K.
Postdoctoral Fellow, 1986-1992, University of California-San Diego, The Scripps Research Institute, and La Jolla Cancer Research Foundation (now the Sanford-Burnham Institute).
Area of Study
Regulation of cell signaling and cancer by Ras family GTPases. More details...
Selected Recent Publications
Rebhun, J.F., Chen, H., and Quilliam, L.A. (2000). Identification and characterization of a new family of guanine nucleotide exchange factors for the Ras-related GTPase Ral. J. Biol. Chem. 275, 13406-13410.
Rebhun, J.F., Castro, A.F., and Quilliam, L.A. (2000). Identification of guanine nucleotide exchange factors for the Rap1 GTPase: regulation of MR-GEF by M-Ras-GTP interaction. J. Biol. Chem. 275, 34901-34908.
Tsygankova, O.M., Saavedra, A., Rebhun, J.F., Quilliam, L.A. and Meinkoth, J.L. (2001). Coordinated regulation of Rap1 and thyroid differentiation by cAMP and PKA. Mol. Cell. Biol. 21, 1921-1929.
Zong, H., Kaibuchi, K. and Quilliam, L.A. (2001). The insert region of Rho is essential for activation of Rho-kinase and cellular transformation. Mol. Cell. Biol.21, 5287-5298.
Mei, F., Qiao, J., Tsygankova, O.M., Meinkoth, J.L., Quilliam, L.A., and Cheng, X. (2002). Differential signaling of cAMP: opposing effect of Epac and PKA on PKB activation. J. Biol. Chem. 277, 11497-11504.
Reuther, G., Lambert, Q.T., Rebhun, J.F., Caligiuri, M.A., Quilliam, L.A. and Der, C.J. (2002). RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia. J. Biol. Chem. 277, 30508-14.
Quilliam, L.A., Rebhun, J.F., and Castro, A.F. (2002) A growing family of guanine nucleotide exchange factors is responsible for the activation of Ras family GTPases [review]. Progress in Nucleic Acid Research and Molecular Biology,71, 391-444.
Zheng, Y., Quilliam, L.A. (2003). Activation of the Ras superfamily of small GTPases. EMBO Rep. 4, 463-8.
Riggins, R.B., Quilliam, L.A., Bouton, A.H. (2003) Synergistic promotion of c-Src activation and cell migration by Cas and AND-34/BCAR3. J Biol Chem.278, 28264-73.
Castro, A.F., Rebhun, J.F., Clark, G.J., Quilliam ,L.A., (2003) Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J Biol Chem.278, 32493-6
Arthur, W.T., Quilliam, L.A., and Cooper, J.A. (2004) Rap1 promotes cell spreading by localizing Rac guanine nucleotide exchange factors. J. Cell Biol. 167, 112-122.
Quilliam, L.A. (2004) Ras Family. In: Encyclopedia of Biological Chemistry, eds: W.J. Lennarz and M.D. Lane, Elsevier, Oxford, Vol. 3, pp 640-644.
Felekkis, K.N., Narsimhan, R.P., Near, R. Castro A.F., Zheng, Y., Quilliam L.A., and Lerner, A. (2005). AND-34 activates phosphatidylinositol 3-kinase and induces anti-estrogen resistance in a SH2 and GDP exchange factor-like domain-dependent manner. Mol. Cancer Res. 3, 32-41.
Wittchen, E.S., Worthylake, R.A., Kelly, P., Casey, P.J., Quilliam, L.A. and Burridge, K. (2005). Rap1 GTPase Inhibits Leukocyte Transmigration by Promoting Endothelial Barrier Function. J. Biol. Chem., 280, 11675-11682.
Castro, A.F., Rebhun, J.F., and Quilliam, L.A. (2005). Measuring Ras-family GTP levels in vivo - running hot and cold. Methods 37(2):190-6.
Quilliam, L.A. (2006). Specificity and expression of RalGPS as RalGEFs. Methods Enzymol 407, 108-14.
Li, Y., Asuri, S., Rebhun, J.F., Castro, A.F. and Paranavitana, N.C., and Quilliam, L.A. (2006). The guanine nucleotide exchange factor, Epac2, couples cyclic AMP and Ras signals at the plasma membrane. J. Biol. Chem. 281, 2506-14.
Ming, W., Li, X., Li, S., Billadeau, D., Quilliam L.A. and Dinauer, M.C. (2007). p67phox regulates phagocyte NADPH oxidase by activating Vav guanine nucleotide exchange activity on Rac. Mol. Cell Biol. 27, 312-23.
Hong, J., Doebele, R.C., Zeitlin, B., Nor, J.E., Quilliam, L.A., Tang, W-J., Lingen, M.W. and Rosner, M.R. (2007). Anthrax edema toxin inhibits endothelial cell chemotaxis via Epac and Rap1. J. Biol. Chem. 282, 19781-7.
Li,Y., Yan, J. De, P. Chang, H.-C. Yamauchi, A. Christopherson II, K. W., Paranavitana, N. C., Peng, X., Kim, C., Munugulavadla, V., Kapur, R., Chen, H., Shou, W., Stone, J. C., Kaplan, M. H., Dinauer, M. C., Durden, D. L., and Quilliam, L.A. (2007). rap1A null mice have altered myeloid cell functions suggesting distinct roles for the closely related Rap1a and 1b proteins. J. Immunol. 179. 8322-31.
Quilliam. L.A. (2007). New insights into the mechanisms of SOS activation. Sci. STKE 2007, pe67.
Yan, J. Li, F., Ingram, D.A., and Quilliam, L.A. (2008). Rap1a serves as a key regulator of FGF2-induced angiogenesis and together with Rap1b controls human endothelial cell functions Mol. Cell. Biol. 28, 5803-10.
Asuri, S., Yan, J., Paranavitana, N.C., and Quilliam L.A. (2008). E-cadherin dis-engagement activates the Rap1 GTPase J. Cell. Biochem. (Epub ahead of print Sept 2nd).
Woolfrey, K., Srivastava, D.P., Photowala, H., Yamashita, M., Barbolina, M.V., Cahill, M., Xie, Z., Jones, K.A., Quilliam, L.A., Prakriya, M., and Penzes, P. (2009). Epac2 promotes synapse dynamic remodeling and depression, and its disease-associated variants affect spine morphology. Nature Neurosci. 12, 1275-84.
Panchatcharam, M., Miriyala S., Yang, F., Leitges, M., Chrzanowska-Wodnicka, M., Quilliam, L.A., Anaya, P., Morris, A.J., and Smyth, S.S. (2010). Hyperglycemic stress exacerbates vascular smooth muscle cell responses through integrin αVβ3 signaling. Intl. J. Biochem. Cell Biol. 42, 964-974.
Awasthi, A., Samarakoon , A., Chu, H., Quilliam, L.A., White II, G.G., Chrzanowska-Wodnicka, M. and Malarkannan, S. (2010) Rap1b regulates NK cell functions via IQGAP1-mediated signalosomes. J. Exp. Med. 207, 1923-38.
Kepner, E.M., Yoder, S.M., Oh, E., Kalwat, M.A., Wang, Z., Quilliam, L.A. and Thurmond D.C. (2011). Cool-1/βPIX functions as a guanine nucleotide exchange factor (GEF) in the cycling of Cdc42 to regulate insulin secretion. Am. J. Physiol Endocrinol Metabol. 301, E1072-E1080.
Bai, Y., Luo, Y., Liu, S., Zhang, L., Shen, K., Dong, Y., Walls, C.D., Quilliam, L.A., Wells, C.D., Cao, Y., and Zhang, Z-Y. (2011). PRL-1 promotes ERK1/2 and RhoA activation through a non-canonical interaction with the Src Homology 3 Domain of p115 Rho GTPase-activating Protein. J. Biol. Chem. 286, 42316-42324.
Babcock, J.T. and Quilliam, L.A. (2011). Rheb/mTOR Activation and Regulation in Cancer: Novel Treatment Strategies Beyond Rapamycin. Curr Drug Targets 12: 1223-31.
Castro A.F., Campos, T., Babcock, J.T., Armijo, M.E., Martinez-Conde, A., Pincheira, R., and Quilliam, L.A. (2012). M-Ras induces Ral and JNK activation to regulate MEK/ERK-independent gene expression in MCF-7 breast cancer cells. J. Cell. Biochem. 113, 123-64.
Jeyaraj, S., Unger, N., Eid, A., Mitra, S., El-Dahdah, N., Quilliam, L.A., Flavahan, N., and Chotani, C. (2012) Cyclic AMP-Rap1A Signaling Activates RhoA to Induce α2C-Adrenoceptor Translocation to the Cell Surface of Microvascular Smooth Muscle Cells. Am. J. Physiol. - Cell. Physiol. 303, C499-511.
Siroky, B.J., Yin, H., Babcock, J.T., Lu, L., Hellmann, A.R., Dixon, B.P., Quilliam, L.A. and Bissler, J.J. (2012). Human TSC associated renal angiomyolipoma cells are hypersensitive to ER stress. Am. J. Physiol. - Renal Physiol. 303, F831-44.
Nguyen, H.B. and Quilliam, L.A. (2012). Rap GEF Family. In Encyclopedia of Signaling Molecules, ed: S. Choi, Springer, New York. Chapter 274, pp 1590-96.
Crotzer, V.L., Matute, J.D., Arias, A.A., Zhao, H., Quilliam, L.A., Dinauer, M.C. and Blum, J.S. (2012). Cutting Edge: Defects in NADPH oxidase p40phox impact MHC class II antigen presentation by B lymphoblasts. J. Immunol. 189, 3800-4.
Nguyen, H.B., Babcock, J.T., Wells, C.D. and Quilliam, L.A. (2013). LKB1 tumor suppressor regulates AMP kinase/mTOR independent cell growth and proliferation via the phosphorylation of Yap. Oncogene (Epub ahead of print, Oct 1).
Quilliam, L.A. (Feb, 2013). Ras family. In: W.J. Lennarz and M.D. Lane (eds) The Encyclopedia of Biological Chemistry, 2nd edition, Vol 4, Ch. 322: 167-71. Waltham, MA, Academic Press.
Schmid, M.C., Franco, I., Kang, S.W., Hirsch, E., Quilliam, L.A. and Varner, J.A. (2013). PI3-Kinase Γ Promotes Rap1a-Mediated Activation of Myeloid Cell Integrin α4β1, Leading to Tumor Inflammation and Growth. PLoS One 8(4):e60226.
Babcock, J.T., Nguyen, H.B., He, Y., Wek, R.C., and Quilliam, L.A. (2013). Mammalian target of rapamycin complex 1 (mTORC1) enhances bortezomib-induced death in tuberous sclerosis complex (TSC)-null cells by a c-MYC-dependent induction of the unfolded protein response. J. Biol. Chem. 288, 15687–15698.
This laboratory is interested in delineating signal transduction pathways induced by growth-stimulatory factors, and in determining the mechanisms by which these pathways are aberrantly activated during the course of malignant transformation. Many of the genes that become mutated in human cancers encode for mitogenic signaling proteins. It is anticipated that characterization of the enzymes and protein:protein interactions involved in mitogenic signaling will form the basis for the rational design of novel anti-cancer therapeutics.
Research is primarily focused on understanding the biological function of Ras family GTPases and the upstream guanine nucleotide exchange factors (GEFs) that regulate them. Ras proteins are a large family of cellular signaling molecules that mediate a variety of growth-promoting functions. The prototypic Ras proteins, H-, K-, and N-Ras, are mutationally activated in ~30% of human cancers and have been extensively studied. We are currently defining the roles of three Ras-related proteins, M-Ras, Rap1A and Rheb. We are examining the role of downstream effector pathways in mediating M-Ras-induced cell growth and transformation and have found that M-Ras might signal through Rap1.
Rap1 is a ubiquitously expressed protein that fulfills an essential role in eukaryotic cell function as proven by the embryonic lethality of Rap1-deficient flies. Rap1 has been identified as a key regulator of several adhesion-related events including phagocytosis, migration, and cell-cell contact. However, what triggers Rap1 activation and what downstream targets Rap1 employs to regulate cellular adhesion remain to be determined. We are using cell culture and a mouse genetic model to answer some of these questions in solid tissue and hematopoeitic cells.
Rheb has recently been implicated as the target of the TSC2 tumor suppressor. As such it may contribute to tumor formation or debilitating TSC-linked diseases such as lymphangioleiomyomatosis in patients that inherit or acquire TSC1 or TSC2 mutations. Since Rheb is upstream of mTOR (mammalian target of rapamycin) and is a farnesylated protein, the immuno-suppressant drug, rapamycin, or the farnesyltransferase inhibitors originally designed to block Ras-induced cancer might now be used to treat tumors involving the Akt/TSC2/Rheb/mTOR signal transduction pathway.
Ras family proteins are GTPases that switch between inactive GDP- and active GTP-bound states in response to extracellular stimuli. This activation event is mediated by guanine nucleotide exchange factors (GEFs) that swap GDP for GTP enabling a conformational change and activation of Ras family proteins. We have recently identified several novel GEFs that act on Rap1, M-Ras and another GTPase, Ral. One of these exchange factors has been implicated in estrogen-independent growth of breast cancer cells. Therefore, we are establishing how hormone and growth factor stimulation leads to the recruitment and activation of these novel GEFs and whether the activation of these proteins plays a role in cellular transformation. Finally we have found that the presence of Ras association (RA) domains in the regulatory regions of several GEFs enables them to initiate GTPase cascades and/or cross-talk between Ras family members. We are examining the implications of this cross talk on biological events.
Guanine nucleotide exchange factors (GEFs) are responsible for coupling extracellular signals to Ras protein activation.
GEFs contain a core CDC25 homology (catalytic) domain that contains 3 structurally conserved regions (scr) plus variable regulatory sequences. GEFs recently identified/characterized in this lab that regulate several Ras-related GTPases are hi-lighted in the cream box. RalGPS regulates Ral, GRP3 acts on multiple GTPases including Ras, M-Ras and Rap1 while PDZ-GEF and MR-GEF regulate Rap1 and 2. We are currently addressing the role of these proteins in cellular regulation.
Rheb is a target of farnesyl transferase inhibitors.
Studies by this and several other laboratories identified the tumor suppressor protein TSC2/Tuberin as a GTPase activating protein (GAP) for the Ras-related protein, Rheb. This placed Rheb in the mTOR pathway that regulates protein synthesis. Because Rheb is post translationally modified by the same farnesyl transferase that adds a lipid moiety to Ras, enabling it to associate with cellular membranes (essential for Rasfunction) we are examining whether farnesyl transferase inhibitors (FTIs) can also block Rheb function. This may be of particular benefit in e.g. glioblastoma where ~50% of patients have increased signaling through this pathway due to loss of the tumor suppressor PTEN or in tuberous sclerosis where loss of TSC1 and 2 leads to Rheb-GTP accumulation.
Ras family proteins are associated with GTPase/GEF cascades.
Several of theGEFs in Fig. 1 have Ras-association (RA) domains that enable them to be regulated by related Ras family members. This results in the formation of cascades whereby the activation of one GTPase might lead to the subsequent activation of another. A major role of Ras-GEF binding may be to relocalize the GEF in a certain place in the cell, resulting in activation of the downstream substrate only in that micro-environment. For example, recruitment of MR-GEF to the plasma membrane by M-Ras will limit Rap1 activation to the cell periphery, leaving other Rap1 molecules, e.g. on intracellular organelles/vesicles, untouched.