Personal HistoryAfter receiving my Ph.D. degree from the University of Kansas in Biochemistry, I completed a postdoctoral fellowship at the University of Notre Dame in the Department of Chemistry with Dr. Frances Castellino. Following this, I joined the American Red Cross Research Laboratories in 1982. While employed at the American Red Cross, I was academically affiliated with The George Washington University and in 1995 was appointed as Professor in the Department of Biochemistry and Molecular Biology. In 1997, I became Head of the Department of Vascular Biology at the American Red Cross. I joined the University of Maryland in 2004 as Professor of Surgery and Physiology, and was appointed Director of the Center of Vascular and Inflammatory Diseases in 2005.
• Lipoprotein & protease receptors
• cell migration
• Alzheimer disease
• Vascular biology
• PDGF receptor
• macrophages and their role in inflammation
The low density lipoprotein (LDL) receptor-related protein (LRP) is a large cellular receptor that not only functions as important cargo transporters, but also informs the cell of changes in its environment by mediating signaling responses. LRP is a member of the LDL receptor superfamily, and binds 30 or more ligands. Their cargo transport by LRP is closely associated with regulation of cellular physiology and cellular signaling events. A goal of studies in our laboratory is to understand the role of LRP in modulating cell signaling events and how this affects development of certain diseases.
Role of LRP in atherosclerosis.
Smooth muscle cells play an important role in the maintenance of vessel wall integrity, and undergo proliferation in response to injury. Interestingly, a role for LRP in smooth muscle biology was established some time ago, when it was demonstrated that LRP antibodies inhibited smooth muscle cell migration. More recent studies have found that LRP is atheroprotective, and prevents proliferation of smooth muscle cells in response to injury. This occurs by regulation of platelet derived growth factor (PDGF) receptor, a receptor tyrosine kinase that is activated upon binding PDFG. PDGF induces a transient tyrosine phosphorylation of the LRP cytoplasmic domain in a process dependent on PDGF receptor activation, and may have important consequences in PDGF initiated signaling. Studies are now underway to identify the functional role LRP plays in modulating PDGF signaling pathways.
Role in inflammation.
Chronic inflammation is a key feature of atherosclerosis. During the development of this disease, monocytes are recruited to the vessel wall where they differentiate into macrophages and greatly accelerate plaque formation and the progression of this disease. Many ligands recognized by LRP are generated during inflammation and/or wound repair, which has led us to hypothesize that LRP functions to modulate the inflammatory response, and our laboratory is investigating this hypothesis by studying the role of LRP in macrophages.
Role of LRP in Alzheimers disease.
The brain of an Alzheimer patient is marked by two major abnormalities: neurofibrillary tangles and amyloid (or senile) plaques. Neurofibrillary tangles are bundles of protein filaments found inside nerve cells, and senile plaques are clusters of amyloid surrounded by dead or dying cells. These plaques are mainly composed of a small peptide, called beta amyloid (Abeta), which is derived from a much larger precursor protein called beta amyloid precursor protein (APP). Other than manufacturing the protein that becomes a plaque that can lead to Alzheimer disease, the function of APP in the body is unknown. Abeta deposition is an important pathological step in Alzheimer disease, and reflects an imbalance of Abeta synthesis and clearance. Several pathways that impact Abeta production and clearance converge on LRP. This multifunctional receptor can help clear Abeta peptide under certain conditions, while under other conditions can increase production of this peptide. Studies in the laboratory are currently underway to investigate these pathways.
Anna Lillis, graduate student
Christopher Newton, Graduate Student
Chun-Xiang Liu, Postdoctoral fellow
Elizabeth Hahn-Dantona, Postdoctoral Fellow
Fran Battey, Research Supervisor
Irina Mikhailenko, Research Associate
Molly Migliorini, Research Supervisor
Sripriya Ranganathan, Assistant Professor
Susan Robinson, Research Supervisor
Kounnas, M.Z., Moir, R.D., Rebeck, G.W., Bush, A.I., Argraves, W.S., Tanzi, R.E., Hyman, B.T., and Strickland, D.K. (1995) LDL receptor-related protein, a multifunctional apoE receptor, binds secreted beta-amyloid precursor protein and mediates its degradation. Cell, 82, 331-340
Ulery, P.G. , Beers, J., Mikhailenko, I., Tanzi, R.E., Rebeck, G.W., Hyman, B.T. and Strickland, D.K. (2000) Modulation of beta-amyloid peptide generation by the LDL receptor-related protein: Evidence that LRP contributes to the pathogenesis of Alzheimers Disease J. Biol. Chem. 275, 7410-7415
Herz, J. and Strickland, D.K. 2001 LRP: A multifunctional scavenger and signaling receptor. J. Clin. Invest. 108, 779-784
Loukinova, E., Ranganathan, S., Kuznetsov, S., Gorlatov, N., Migliorini, M.M., Loukinov, D., Ulery, P.G., Mikhailenko, I., Lawrence, D.A., Strickland, D.K. (2002) PDGF-induced tyrosine phosphorylation of the LDL receptor-related protein (LRP): Evidence for integrated co-receptor function between LRP and the PDGF receptor. J.Biol.Chem: 277:15499-506
Migliorini, M., Behre, E., Brew, S., Ingham, K.C., and Strickland, D.K. (2003). Allosteric modulation of ligand binding to LRP by RAP requires critical lysine residues within its carboxy-terminal domain. J. Biol. Chem. 278, 17986-17992
Makarova, A., Mikhailenko, I., Bugge, T.H., List, K., Lawrence, D. A., and Strickland, D.K. (2003) The LDL receptor related protein modulates protease activity in the brain by mediating the cellular internalization of both neuroserpin and neuroserpin:tPA complexes. J. Biol. Chem. 278, 50250-50258
Yepes, M., Sandkvist, M., Moore, E., Bugge, T.H., Strickland, D.K., and Lawrence, D.A. (2003). Tissue-type plasminogen activator induces opening of the blood-brain barrier via the low density lipoprotein receptor-related protein. J. Clin. Inves. 112, 1533-1540
Ranganathan,S., Liu,C.X., Migliorini,M.M., Von Arnim,C.A., Peltan,I.D., Mikhailenko,I., Hyman,B.T., and Strickland,D.K. 2004. Serine and threonine phosphorylation of the LDL receptor-related protein (LRP) by protein kinase Calpha regulates endocytosis and association with adaptor molecules. J Biol Chem 279:40536-44
Newton, C.S., Loukinova, E. Mikhailenko, I., Ranganathan, S., Gao, Y., Haudenschild, C., and Strickland, D.K. (2005) Platelet-derived growth factor receptor-beta (PDGFR-beta) activation promotes its association with the LDL receptor-related protein (LRP): Evidence for co-receptor function. J. Biol. Chem. 280(30):27872-8
Lillis, A.P., Mikhailenko,I and Strickland, D.K. (2005) Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability. J. Thrombosis Heamostasis 3(8):1884-93.
Cao, C., Lawrence, D.A., Li, Y., Von Arnim, C.A., Herz, J., Su, E.J., Makarova, A., Hyman, B.T., Strickland, D.K., and Zhang, L. (2006) Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration. EMBO Journal 25(9):1860-70
Lee, D., Walsh, J.D., Mikhailenko, I., Yu, P., Migliorini, M., Wu, Y. Krueger,S., Curtis, J.E., Harris, B., Lockett, S., Strickland, D.K., and Wang, Y-X. (2006) The Receptor Associated Protein Uses a Histidine Switch to Modulate its Interaction with the LDL Receptor Related Protein (LRP) in the ER and Golgi Molecular Cell 22, 423-430