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 Steve Caplan
- Associate Professor Biochemistry and Molecular Biology
Ph.D., Hebrew University, Jerusalem, 1998
Phone: (402) 559-7556 (Office)
(402) 559-7559 (Lab)
Fax: (402) 559-6650
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- Email: scaplan@unmc.edu
Click here for biographical sketch and further publications.
Molecular mechanisms controlling endocytic recycling and internalization.
The primary research interests of this lab focus on studying the molecular mechanisms regulating the recycling of cell surface proteins and other molecules back to the plasma membrane.
The internalization of cell surface molecules from the plasma membrane is a critical event for all eukaryotic cells. While many internalized molecules are degraded in the endo-lysosomal pathway, many receptors, proteins and other molecules undergo sequential rounds of recycling back to the plasma membrane. Endocytic recycling is key for the control of cell surface receptors on the plasma membrane. Since most receptors generally transduce signals only when bind ligands at the plasma membrane (PM), this means that regulation of their localization to the PM may have a critical impact on signal transduction, and cell proliferation, which is directly related to cancer. Endocytic recycling also governs the flow of nutrients into the cell, and can compensate for the loss of membrane lipids incurred during the process of internalization. Other specialized recycling functions include: synaptic vesicle recycling, iron homeostasis in liver, MHC Class II and MHC Class I molecules, transcytosis of Transferrin receptor and Immunoglobulin A (IgA) across polarized epithelial cells, and insulin-dependent glucose transport in muscle and adipose cells.
Upon internalization, cargo molecules andocytosed in vesicles fuse rapidly with early endosomes (EE), also known as sorting endosomes (SE). At the EE/SE, sorting events occur to regulate whether cargo molecules are destined for degradation, or returned to the plasma membrane. Recycling to the plasma membrane occurs by at least two distinct pathways: 1) directly from EE/SE, and 2) via a juxtanuclear endocytic recycling compartment (ERC) [see Figure 1].
We have been studying the involvement of the C-terminal EH-domain containing proteins, EHD1-4, in endocytic trafficking events [see Figure 2]. Our laboratory has been involved in defining and characterizing the functions of these fascinating proteins and in understanding how they coordinate the regulation of endocytic events with the Rab family of small GTP-binding proteins. Accordingly, we have identified two Rab effectors that interact with EHD proteins, and elucidated the mode by which they cooperate in the regulation of endocytic transport.
We are also particularly interested in understanding the molecular and atomic mechanisms by which EHD1 and its paralogs function. We have solved the NMR solution structure of the EHD1 EH-domain, and identified interesting structural differences between this domain and other EH-domains [see Figure 3].
One of the hallmarks of EHD1 is its localization to a unique array of tubular and vesicular membrane structures [see Figure 4]. Since our observing the existence of these structures in 2002, a major question in the field has been concerned with their composition and function. Our recent and ongoing studies have identified specific phosphoinositides as components of the tubules, and we have defined a critical role for EHD1-containing membrane tubules to facilitate efficient receptor recycling.
Our underlying philosophy is that no technique should be a barrrier to answer important biological questions. Therefore, for our research we collaborate with multiple laboratories at UNMC and around the world to utilize state-of-the-art technologies that range from cell biological, biochemical, immunological, biophysical, structural and optical (microscopy). More specifically, these techniques include qualitative and quantitative confocal microscopy analysis and flow cytometry-based analysis coupled with endocytic function assays, an array of protein-protein interaction techniques including immunoprecipitations, GST-fusion protein pulldown assays coupled with mass spectrometry, yeast two-hybrid analysis and surface plasmon resonance, molecular biology (cloning and engineering of proteins), protein purification, antibody generation, purification and testing, etc.
We welcome new prospective students who are extremely highly motivated.
RECENT PUBLICATIONS:
Naava Naslavsky, Juliati Rahajeng, Mahak Sharma, Marko Jovic and Steve Caplan*. A novel interaction between EHD3 and Rab11-FIP2 links EHD-family proteins to Rab11-mediated transport. Mol. Biol. Cell, 2006, 17:163-177. Abstract
Deborah Rapaport, Wojtek Auerbach, Naava Naslavsky, Metsada Pasmanik-Chor, Emilia Galperin, Amos Fein, Steve Caplan, Alexandra L. Joyner, and Mia Horowitz. Recycling to the plasma membrane is delayed in EHD1 knockout mice. Traffic, 2006, 7:52-60. Abstract
Masato Maeda, Emhonta Johnson, Shymali Mandal, Kathryn R. Lawson, Robert A. Svoboda, Steve Caplan, Keith R. Johnson and Margaret J. Wheelock. Expression of inappropriate cadherins by epithelial tumor cells promotes endocytosis and degradation of E-cadherin via competition for p120ctn. Oncogene, 2006, 25:4595-4604. Abstract
Marko Jovic, Naava Naslavsky, Debora Rapaport, Mia Horowitz and Steve Caplan*. EHD1 regulates b1 integrin endosomal transport: effects on focal adhesions, cell spreading and migration. J. Cell Sci., 2007, 120:802-814. Abstract
Naava Naslavsky, Juliati Rahajeng, Debora Rapaport, Mia Horowitz and Steve Caplan*. EHD1 regulates cholesterol homeostasis and lipid droplet storage. Biochem. Biophys. Res. Comm., 2007, 357:792-799. Abstract
Naava Naslavsky, Juliati Rahajeng, Sylvie Chenavas, Paul L. Sorgen* and Steve Caplan*. EHD1 and Eps15 interact with phosphatidylinositols via their EH-domains. J. Biol. Chem., 2007, 282:16612-16622. Abstract
Joseph T. Roland, Anne K. Kenworthy, Johan Peranen, Steve Caplan and James R. Goldenring. Rab8a interacts with Myosin Vb on a tubular network containing EHD1 and EHD3. Mol. Biol. Cell, 2007, 18:2828-2837. Abstract
Fabien Kieken, Marko Jovic, Naava Naslavsky, Steve Caplan* and Paul L. Sorgen*. NMR structure note: EH domain of EHD1.# J. Biomolecular NMR, 2007, 39:323-329. Abstract
Jianuo Liu, Jamie Lin, Thomas V. Johnson, S.H. Ramirez, Tatianna K. Bronich, Steve Caplan, Yuri Persidsky, Howard E. Gendelman and Jonathan Kipnis. T cell mechanism for copolymer-1-induced neuroprotein. Eur. J. Immunol., 2007, 37(11):3143-3154. Abstract
Mahak Sharma, Naava Naslavsky and Steve Caplan*. EHD4 regulates early endosome transport and biogenesis. Traffic Epub 2008 Mar 6, June 9(6):995-1018. Abstract
Amit Tuli, Mahak Sharma, Naava Naslavsky, Steve Caplan, and Joyce C. Solheim. Specificity of Amyloid Precursor-like Protein 2 Interactions with MHC Class I Molecules. Immunogenetics Jun;60(6):303-13, Epub 2008 May. Abstract
Amit Tuli, Mahak Sharma, Xiaojian Wang, Naava Naslavsky, Steve Caplan, and Joyce C. Solheim. Amyloid precursor-like protein 2 increases the endocytosis, instability, and turnover of the H2-K(d) MHC class I molecule. J. Immunol., 2008, 181:1978-1987. Abstract
Barth D. Grant and Steve Caplan*. Mechanisms of EHD/RME-1 protein function in endocytic transport. Traffic 2008, 9:2043-2052. Abstract
Paul Bowness, Steve Caplan and Michael Edidin. MHC molecules lead many lives. Workshop on MHC Class I molecules at the interface between Biology & Medicine. EMBO Rep., Jan. 2009, 10(1):30-34, Epub 2008 Dec 5. Abstract
Naava Naslavsky, Jenna McKenzie, Nihal Altan-Bonnet, David Sheff and Steve Caplan*. EHD3 regulates early endosome-to-Golgi transport and preserves Golgi morphology. J. Cell Sci., 2009, 122:389-400. Abstract
Amit Tuli, Mahak Sharma, Xiaojian Wang, Laura C. Simone, Haley L. Capek, Steven Cate, William H. Hildebrand, Naava Naslavsky, Steve Caplan and Joyce C. Solheim. Amyloid precursor-like protein 2 association with HLA class I molecules. Cancer Immunol. Immunother., published online Jan. 31, 2009. Abstract
Marko Jovic, Mahak Sharma, Juliati Rahajeng and Steve Caplan*. The early endosome: a busy sorting station for proteins at the crossroads. Histol. Histopathol, in press, 2009.
Marko Jovic, Fabien Kieken, Naava Naslavsky, Paul Sorgen* and Steve Caplan*. EHD1-associated tubules contain phosphatidylinositol-4-phosphate and phosphatidylinositol-(4,5)-bisphosphate and are required for efficient recycling. Mol. Biol. Cell, 2009, 20:2731-2743. Abstract
Mahak Sharma, Marko Jovic, Fabien Kieken, Naava Naslavsky, Paul Sorgen* and Steve Caplan*. A model for the role of EHD1-containing membrane tubules in endocytic recycling. Communicative and Integrative Biology, in press, 2009.
Saumya Pant, Mahak Sharma, Kruti Patel, Steve Caplan, Chavela M. Carr and Barth Grant. AMPH-1/Amphiphysin/Bin1 functions with RME-1/Ehd in endocytic recycling. Nat. Cell Biol., in press, 2009.
Amit Tuli, Mahak Sharma, Haley L. Capek, Naava Naslavsky, Steve Caplan and Joyce C. Solheim. Amyloid precursor-like protein 2 reduces major histocompatibility complex class I molecule surface expression via clathrin-mediated endocytosis and lysosomal degradation. J. Biol. Chem., in press, 2009.
Fabien Kieken, Marko Jovic, Naava Naslavsky, Steve Caplan* and Paul Sorgen*. Structural mechanisms for NPF, DPF and GPF interaction with the C-terminal EH-domain of EHD1. Protein Science, in press, 2009.
Mahak Sharma, Sai Srinivas Panapakkam Giridharan, Juliati Rahajeng, Naava Naslavsky* and Steve Caplan*. MICAL-L1 links EHD1 to tubular recycling endosomes and regulates receptor recycling. Mol. Biol. Cell, in press, 2009.
*Corresponding author
#Structure from paper chosen for cover of J. Biomolecular NMR for 2008.
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