Professor, Biochemistry and Molecular Biology, Chair of Department Graduate Committee

Steve Capalan, PhDPhone: 402-559-7556 (Office)
402-559-7559 (Lab)
Fax: 402-559-6650
Email: scaplan@unmc.edu

View Dr. Caplan's personal website

View the Caplan Lab personnel. 

Dr. Caplan is a recipient of the 2008 UNMC Distinguished/New Investigator Award and a 2010 recipient of the UNMC Distinguished Investigator Award.  He also received UNMC's Outstanding Faculty Mentor of Graduate Students Award in 2011, and the Thomas Maciag Award in 2012, a national award for combined research excellence and mentorship.  He serves on the editorial board of The Journal of Biological Chemistry and PLoS One, chairs a review committee at the American Heart Association, and reviews ad hoc at the NIH. 

Congratulations to Dr. Marko Jovic (National Institutes of Health), and Dr. Mahak Sharma (Harvard University), the first two students to graduate from the Caplan laboratory. Both Marko and Mahak are sequential recipients of the prestigious Thomas Jefferson Award (awarded each cycle to a single graduating student) for their ingenuity and extensive productivity in their doctoral research!

Education/Training:
Ph.D., Hebrew University, Jerusalem, 1998 

Research:

Student Rotation Opportunities Available

Rotation opportunities are available for highly motivated Biochemistry and Molecular Biology, MD/PhD, BRTP and CRGP students. Contact Dr. Caplan for additional information (scaplan@unmc.edu).

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].

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.

Figure 2

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].

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.

Figure 4 

Our underlying philosophy is that no technique should be a barrier 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 pull-down 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:

Paul Bowness, Steve Caplan and Michael Edidin. MHC molecules lead many lives. Workshop on MHD Class I molecules at the interface between Biology & Medicine. EMBO Rep., 2009, 1:30-34.

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.

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.

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., 2009, 58:1419-1431.

Marko Jovic, Mahak Sharma, Juliati Rahajeng and Steve Caplan*. The early endosome: A busy sorting station for proteins at the crossroads. Histopathol., 2010, 25(1):99-112.

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. Commun. Integr. Biol., 2009, 2:431-433.

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., 2009, 11:1399-1410.

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., 284:34296-34307.

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, 2009, 18:2471-2479.

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, 2009, 20:5181-5194.

Juliati Rahajeng, Steve Caplan* and Naava Naslavsky*. Vps45 modulates Rabenosyn-5 expression and regulates transport at multiple trafficking routes. Exp. Cell Res., 2010, 316:859-874.

Fabien Kieken, Mahak Sharma, Marko Jovic, Sai Srinivas Panapakkam Giridharan, Naava Naslavsky, Steve Caplan*, and Paul Sorgen*. Mechanism for the selective interaction of C-terminal EH-domain proteins with specific NPF-containing partners. J. Biol. Chem., 2010, 285:8687-94. *Indicates co-corresponding authors.

Souvik Chakraborty, Shalini Mitra, Matthias M. Falk, Steve Caplan, Margaret J. Wheelock, Keith R. Johnson, and Parmender P. Mehta. E-cadherin differentially regulates the assembly of Connexin43 and Connexin32 into gap junctions in human squamous carcinoma cells. J. Biol. Chem., 2010, 285:10761-10776.

Mahak Sharma, Sai Srinivas Panapakkam, Giridharan, Juliati Rahajeng, Steve Caplan* and Naava Naslavsky*. MICAL-L1: an unusual Rab effector that links EHD1 to tubular recycling endosomes. Communicative and Integrative Biology, 2010, 3:1-3.

Chan Choo Yap, Zofia M. Lasiecka, Steve Caplan and Bettina Winckler. Alterations of EHD1/EHD4 protein levels disrupt axonal targeting of L1/NgCAM. J. Neuroscience, 2010, 30:6646-6657.

Juliati Rahajeng, Sai Srinivas Panapakkam Giridharan, Bishuang Cai, Naava Naslavsky, and Steve Caplan*. Important relationships between Rabs and MICAL proteins in endocytic trafficking. World J. Biol. Chem., 2010, 1(8):254-264.

Juliati Rahajeng, Sai Srinivas Panapakkam Giridharan, Naava Naslavsky*, and Steve Caplan*. Collapsin response mediator protein-2 (Crmp2) regulates trafficking by linking endocytic regulatory proteins to dynein motors. Report/Accelerated Publication J. Biol. Chem., 2010, 285:31918-22.

Zofia Lasiecka, Chan choo Yap, Steven Caplan, and Bettina Winckler. Neuronal early endosomes require EHD1 for L1/NgCAM trafficking. J. Neuroscience, 2010, 30:16485-16497.

Naava Naslavsky and Steve Caplan*. EHD proteins: Key conductors of endocytic transport. Trends Cell Biol. 2011, 21(2):122-31.

Sai Srinivas Panapakkam Giridharan, Jennifer L. Rohn, Naava Naslavsky and Steve Caplan*. Differential regulation of actin microfilaments by human MICAL proteins. J. Cell Sci., in press, 2012.

Juliati Rahajeng, Sai Srinivas Panapakkam Giridharan, Bishuang Cai, Naava Naslavsky, Steve Caplan*. MICAL-L1 is a tubular endosomal membrane hub that connects Rab35 and Arf6 with Rab8a. Traffic, 2012, 13:82-93.

Jing Zhang, Naava Naslavsky and Steve Caplan*. Rabs and EHDs: alternate modes for traffic control. Biosci. Rep., 2012, 32:17-23.

Hayley L. Peters, Amit Tuli, Mahak Sharma, Naava Naslavsky, Steve Caplan, Richard G. MacDonald and Joyce C. Solheim. Regulation of major histocompatibility complex class I molecule expression on cancer cells by amyloid precursor-like protein 2. Immunologic Research, 2011, 51:39-44.

Jing Zhang, Calliste Reiling, James B. Reinecke, Iztok Prislan, Luis A. Marky, Paul L. Sorgen,Naava Naslavsky* and Steve Caplan*. Rabankyrin-5 interacts with EHD1 and Vps26 to regulate endocytic trafficking and retromer function. Traffic, 2012, 13:745-57.

Bishuang Cai, Steve Caplan and Naava Naslavsky. cPLA2a and EHD1 interact and regulate the vesiculation of cholesterol-rich GPI-anchored protein-containing endosomes. Mol. Biol. Cell, 2012, 23:1874-1888.

Sai Srinivas Panapakkam Giridharan, Bishuang Cai, Naava Naslavsky and Steve Caplan*. Trafficking cascades mediated by Rab35 and its membrane hub effector, MICAL-L1. Communicative and Integrative Biology, 2012, 1;5(4):384-387.

Jenna E. McKenzie, Brent Raisley, Xin Zhou, Naava Naslavsky, Tomohiko Taguchi, Steve Caplan and David Sheff. Retromer guides STxB and CD8-M6PR from early to recycling endosomes, EHD1 guides STxB from recycling endosome to Golgi. Traffic, 2012, 13:1140-59.

Jing Zhang, Naava Naslavsky and Steve Caplan*. EHDs meet the retromer: complex regulation of retrograde transport. Cellular Logistics, 2012, in press.

* Corresponding author
♣ Chosen as a Featured Article by Nature's Cell Migration Gateway website
# Structure from paper chosen for cover of J. Biomolecular NMR for 2008
$ Chosen as a 'featured article' by Journal of Cell Science's "In This Issue" 

Current Grants and Contracts:

National Institutes of Health
PI: Steve Caplan
5/1/06 - 11/30/16
Molecular Mechanisms Controlling Endocytic Recycling

National Institutes of Health
PI: Kay-Uwe Wagner, Co-Investigator: Steve Caplan
1/1/09 - 12/31/13
Tsg101-a Modulator of ErbB2 Signaling in Breast Cancer

National Institutes of Health Program Grant
PI: Keith Johnson, Mentor: Steve Caplan
7/1/08 - 6/30/13
Nebraska Center for Cellular Signaling

National Institutes of Health
PI: Steve Caplan, Co-Investigator: Paul Sorgen
4/1/10 - 3/31/14
Regulation of EHD Protein Function by Molecular Partner Interactions

National Institutes of Health, NCI 
PI: Melanie Simpson, Co-Investigator: Steve Caplan
12/1/09 - 11/30/14
Effort: Subcontract for $20,000/year

Nebraska Department of Health
PI:  Steve Caplan
7/1/12 - 6/30/13
Regulation of Src Kinase Trafficking in Lung Cancer

National Institutes of Health Grant - Collaborative Proposal
PI: Steve Caplan, Co-Investigator: Naava Naslavsky
7/1/12 - 6/30/13
Nebraska Center for Cellular Signaling

National Institutes of Health Program Grant - Collaborative Proposal
PI, Joyce Solheim, Co-Investigators: Steve Caplan, Naava Naslavsky
7/1/12 - 6/30/13
Nebraska Center for Cellular Signaling

 

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