Assistant Professor, Biochemistry and Molecular Biology
Phone: 402-559-7559 (Office)
PhD, Hebrew University, Jerusalem, 1998
Control of receptor localization to the plasma membrane is central to normal cell function, and dysregulation is the underlying cause for diseases as diverse as atherosclerosis, diabetes and cancer. For example, enhanced recycling of growth factor receptors has been implicated in pancreatic carcinoma, breast cancer and other epithelial tumors. Receptor levels on the plasma membrane depend on the rates of internalization and recycling back to the cell surface. Most recycled receptors are transported from early endosomes to the plasma membrane via a transitory recycling compartment, but the regulation of these steps remains poorly understood.
The recently identified Eps 15 homology (EH)-domain containing proteins: EHD1, EHD2, EHD3, and EHD4, are critical components of the endocytic pathway. We and others have demonstrated distinct but partially overlapping functions for the four EHD proteins, in the endocytic trafficking of receptors internalized both through clathrin-dependent and independent mechanisms. However, the influence of EHD proteins on the regulation of a distinct family of receptors, those coupled to the plasma membrane by a glycosylphosphatidylinositol-(GPI) anchor and residing in cholesterol and glycosphingolipid-enriched rafts™, has yet to be addressed. GPI-anchored proteins (GPI-APs) contain a specific C-terminal signal sequence that allows the covalent coupling of a synthesized GPI moiety to the protein at the cytoplasmic face of the endoplasmic reticulum. The proteins themselves are highly diverse, and include growth factor receptors, adhesion molecules as well as hydrolytic enzymes, complement inhibitors and other key signaling proteins. In addition to signaling, certain GPI-anchored proteins such as the Carcinoembryonic antigen (CEA) family cell adhesion molecule member, CEACAM5, are human tumor markers that function in intercellular adhesion and are highly expressed in tumor cells.
Given the overall significance of GPI-APs in cell signaling, and especially the role of GPI-APs such as CEA-family members in tumorigenesis, the regulation of intracellular trafficking of these proteins warrants a high level of attention. Most surprisingly, little is known about the molecular mechanisms by which CEACAM5 is internalized and recycled. The long-term goals of this project are to understand the fundamental mechanisms controlling intracellular trafficking and transport of GPI-APs through the endocytic pathways, with emphasis on understanding the mode by which EHD proteins regulate these events. Ultimately, these studies will lead to development of new strategies to treat diseases involving traffic and recycling events.
Jovic M, Naslavsky N, Rapaport, D, Horowitz M, and Caplan S. (2007) EHD1 regulates β1 integrin endosomal transport: effects on focal adhesions, cell spreading and migration. J. Cell Sci. 120:802-814. Abstract
Naslavsky N, Rahajeng J, Rapaport D, Horowitz M, Caplan S. (2007) EHD1 regulates cholesterol homeostasis and lipid droplet storage. Biochem Physic Res Commun. 357:792-799. Abstract
Naslavksy N, Rahajeng J, Chenavas S, Sorgen PL, Caplan S (2007) EHD1 and Eps15 interact with phosphatidylinositols via their Eps15 homology domains. J. Biol. Chem. 282:16612-16622. Abstract
Kieken F, Jovic M, Naslavsky N, Caplan S, Sorgen PL. (2007) EH domain of EHD1. J. Biomol. NMR. 39:323-329. Abstract
Tuli A, Sharma M, Naslavsky N, Caplan S, Solheim JC. (2008) Specificity of amyloid precursor-like protein 2 interactions with MHC class I molecules. Immunogenetics. 60(6):303-313. Abstract
Sharma M, Naslavsky N, Caplan S. (2008) A role for EHD4 in the regulation of early endosomal transport. Traffic. 9(6):995-1018. Abstract
Tuli A, Sharma M, Wang X, Naslavsky N, Caplan S, Solheim JC. (2008) Amyloid precursor-like protein 2 increases the endocytosis, instability, and turnover of the H2-K(d) MHC class I molecule. J. Immunol. 181:1978-1987. Abstract
Naslavsky N, McKenzie J, Altan-Bonnet N, Sheff D, Caplan S*. (2009) EHD3 regulates early endosome-to-Golgi transport and preserves Golgi morphology. J. Cell Sci. 122:389-400. Abstract
Tuli A, Sharma M, Capek, HL, Naslavsky, N, Caplan S and Solheim, JC. (2009) 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.
Kieken F, Jovic M, Naslavsky N, Caplan S, and Sorgen, P. (2009) Structural mechanisms for NPF, DPF and GPF interaction with the C-terminal EH-domain of EHD1. Protein Science, 18:2471-2479.
Sharma M, Panapakkam Giridharan SS, Rahajeng J, Naslavsky N*, and Caplan, S*. (2009) MICAL-L1 links EHD1 to tubular recycling endosomes and regulates receptor recycling. Mol. Biol. Cell, 20:51818-5194.
Tuli A, Sharma M, Wang X, Simone LC, Capek HL, Cate S, Hildebrand WH, Naslavsky N, Caplan S, Solheim JC. (2009) Amyloid precursor-like protein 2 association with HLA Class I molecules. Cancer Immunol. Immunother., published online January 31, 2009.
Jovic M, Kieken F, Naslavsky N, Sorgen P, Caplan S. 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.
Sharma M, Jovic M, Kieken F, Naslavksy N, Sorgen P*, Caplan S*. A model for the role of EHD1-containing membrane tubules in endocytic recycling. Commun. Integr. Biol. 2009, 2:431-433.
Rahajeng J, Caplan S*, Naslavsky N*. Common and distinct roles for the binding partners Rabenosyn-5 and Vps45 in the regulation of endocytic and secretory trafficking in mammalian cells. Exp. Cell Res., 2010, 316:859-874.
Kieken F, Sharma M, Jovic M, Giridharan SS, Naslavsky N, Caplan S*, Sorgen P*. Mechanism for the selective interaction of C-terminal EH-domain proteins with specific NPF-containing partners. J. Biol. Chem. 2010, Jan 29. [Epub ahead of print].
NIH Program Grant P20 Rr018759
Nebraska Center for Cellular Signaling
GPI-anchored protein trafficking and signal transduction
7/1/09 - 6/30/12
Surinder K. Batra
William G. Chaney
G. Stanley Cox
Richard G. MacDonald
Parmender P. Mehta
Robert F. Ramaley